Search for Abstracts using Keywords

38,082 Abstracts & Growing Daily. Sourced from the US National Library of Medicine.


Hibiscus sabdariffa extract led to the reduced invasiveness of prostate cancer cells.

Hibiscus sabdariffa leaf has been previously shown to possess hypoglycemic, hypolipidemic, and antioxidant effects, and induce tumor cell apoptosis. However, the molecular mechanisms involved in the anticancer activity of H. sabdariffa leaf extract (HLE) are poorly understood. The object of the study was to examine the anti-invasive potential of HLE. First, HLE was demonstrated to be rich in polyphenols. The results of wound-healing assay and in vitro transwell assay revealed that HLE dose-dependently inhibited the migration and invasion of human prostate cancer LNCaP (lymph node carcinoma of the prostate) cells under non-cytotoxic concentrations. Our results further showed that HLE exerted an inhibitory effect on the activity and expressions of matrix metalloproteinase-9 (MMP-9). The HLE-inhibited MMP-9 expression appeared to be a consequence of nuclear factor-kappaB (NF-κB) inactivation because its DNA-binding activity was suppressed by HLE. Molecular data showed all these influences of HLE might be mediated via inhibition of protein kinase B (PKB, also known as Akt)/NF-kB/MMP-9 cascade pathway, as demonstrated by the transfection of Akt1 overexpression vector. Finally, the inhibitory effect of HLE was proven by its inhibition on the growth of LNCaP cells and the expressions of metastasis-related molecular proteins in vivo. These findings suggested that the inhibition of MMP-9 expression by HLE may act through the suppression of the Akt/NF-kB signaling pathway, which in turn led to the reduced invasiveness of the cancer cells.

Nutrients. 2015 ;7(7):5065-87. Epub 2015 Jun 24. PMID: 26115086


Oral administration of Hibiscus sabdariffa anthocyanins remarkably inhibited progression of NMU-induced leukemia by approximately 33% in rats.

A previous study reported that anthocyanins from roselle (Hibiscus sabdariffa L.) showed significant anticancer activity in human promyelocytic leukemia cells. To explore the antitumor effect of anthocyanin, a roselle bioactive polyphenol in a rat model of chemical-induced leukemia was assayed. Anthocyanin extract of roselle (Hibiscus anthocyanins, HAs) was supplemented in the diet (0.1 and 0.2%). This study was carried out to evaluate the protective effect of HAs on N-nitrosomethylurea (NMU)-induced leukemia of rats. The study employed male Sprague-Dawley rats (n = 48), and leukemia was induced by intravenous injection of 35 mg kg(-1) body weight of NMU dissolved in physiologic saline solution. The rats were divided into four groups (n = 12): control, NMU only, and HAs groups that received different doses of HAs (0.1 and 0.2%) daily, orally, after NMU injection. After 220 days, the animals were killed, and the following parameters were assessed: morphological observation, hematology examination, histopathological assessment, and biochemical assay. When compared with the NMU-only group, HAs significantly prevented loss of organ weight and ameliorated the impairment of morphology, hematology, and histopathology. Treatment with HAs caused reduction in the levels of AST, ALT, uric acid, and MPO. Also, the results showed that oral administration of HAs (0.2%) remarkably inhibited progression of NMU-induced leukemia by approximately 33.3% in rats. This is the first report to demonstrate that the sequential administration of HAs followed by NMU resulted in an antileukemic activity in vivo.

J Agric Food Chem. 2014 Feb 19 ;62(7):1572-80. Epub 2014 Feb 6. PMID: 24471438


Treatment of HNSCC cells with combinations of CUR and RES can be more effective in inhibiting in vivo and in vitro cancer cell growth than the treatment with CUR alone.

The survival rate of head and neck squamous cell carcinomas (HNSCC) patients has not considerably changed over the last two decades. Polyphenols inhibit the growth of cancer cells. We determined whether the combination of Resveratrol (RES) and Curcumin (CUR) enhanced their in vitro and in vivo antitumor activities on HNSCC cell lines compared to the single compounds. We provide evidence that RES potentiated the apoptotic effect and reduced the IC50 of CUR on HNSCC cell lines. The model of compounds interaction indicated the onset of an additive effect of the two compounds compared to the single treatment after decrease of their concentrations. RES+CUR compared to CUR increased the PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of LC3 II simultaneously with the formation of autophagic vacuoles. RES and CUR induced cytoplasmic NF-κB accumulation. RES+CUR administrations were safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) more efficiently than CUR. Overall, combinations of CUR and RES was more effective in inhibiting in vivo and in vitro cancer growth than the treatment with CUR. Additional studies will be needed to define the therapeutic potential of these compounds in combination.

Oncotarget. 2014 Nov 15 ;5(21):10745-62. PMID: 25296980


Curcumin is a potent chemosensitizer to improve the therapeutic index of paclitaxel.

The microtubule-targeting antineoplastic agent, paclitaxel, is highly efficacious against a wide spectrum of human cancers. However, dose-limiting toxicity and development of drug resistance limit its clinical application. Development of novel strategies that overcome chemoresistance and sensitize cancer cells to paclitaxel can enhance the therapeutic effect of this drug. We have previously shown that curcumin, a natural polyphenol, enhances paclitaxel-induced cytotoxicity in vitro through downregulation of nuclear factor (NF)-κB and Akt pathways. This study was undertaken to determine whether this synergism exists in vivo and to elucidate the underlying molecular mechanisms. Mouse cervical multistage squamous cell carcinoma model using 3-methylcholanthrene (3-MC) and a xenograft model of human cervical cancer in nonobese diabetic severe combined immunodeficient (NOD-SCID) mice using HeLa cells were used to evaluate the synergism. We observed that the combined treatment of curcumin and paclitaxel induced a synergestic reduction in the tumor incidence as well as tumor volume of animals compared with the individual treatments of paclitaxel or curcumin, although curcumin alone could not induce any significant effect at the concentration used. The results suggest that a suboptimal concentration of curcumin augments the antitumor action of paclitaxel by downregulating the activation and downstream signaling of antiapoptotic factors and survival signals such as NF-κB, Akt and mitogen-activated protein kinases that have significant roles in proliferation, survival, angiogenesis and metastasis. This study revealed for the first time that 3-MC-induced tumorigenesis in mice is associated with a strong constitutive activation of NF-κB activity. Furthermore, we also observed that pre-exposure of carcinoma cells isolated from 3-MC-induced tumors to curcumin potentiates paclitaxel-induced apoptosis. Overall, the findings of this preclinical study provide a strong rationale for the validation of this combination through clinical trials. As curcumin could effectively downregulate all these survival signals induced by paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of paclitaxel.

Oncogene. 2011 Jul 14 ;30(28):3139-52. Epub 2011 Feb 14. PMID: 21317920


Co-treatments with Uro-A decreased IC50 values for both 5-FU and 5'DFUR and additionally arrested the cell cycle at the G2/M phase.

Chemotherapy increases the overall survival in colorectal cancer (CRC) patients. 5-Fluorouracil (5-FU) remains as a drug of first choice in CRC therapy over the last four decades. However, only 10-15% of patients with advanced CRC respond positively to 5-FU monotherapy. Therefore, new strategies to enhance the 5-FU effectiveness, overcome the tumor cell resistance and decrease the unspecific toxicity are critically needed. Urolithin A (Uro-A) is the main metabolite produced by the human gut microbiota from the dietary polyphenol ellagic acid. Uro-A targets the colonic mucosa of CRC patients, and preclinical studies have shown the anti-inflammatory and cancer chemopreventive activities of this metabolite. We evaluated here whether Uro-A, at concentrations achievable in the human colorectum, could sensitize colon cancer cells to 5-FU and 5'DFUR (a pro-drug intermediate of 5-FU). We found that both 5-FU and 5'DFUR arrested the cell cycle at the S phase by regulating cyclins A and B1 in the human colon cancer cells Caco-2, SW-480 and HT-29, and also triggered apoptosis through the activation of caspases 8 and 9. Co-treatments with Uro-A decreased IC50 values for both 5-FU and 5'DFUR and additionally arrested the cell cycle at the G2/M phase together with a slight increase in caspases 8 and 9 activation. Overall, we show that Uro-A potentiated the effects of both 5-FU and 5'DFUR on colon cancer cells. This suggests the need for lower 5-FU doses to achieve similar effects, which could reduce possible adverse effects. Further in vivo investigations are warranted to explore the possible role of Uro-A as a chemotherapy adjuvant.

Food Funct. 2015 May ;6(5):1460-9. PMID: 25857357


A methanol extract of wheat grass demonstrated antileukemic potential that might be due to the presence of flavonoids and polyphenolics in it.

OBJECTIVES: Wheat grass (Triticum aestivum) is a gift of nature given to mankind. A number of scientific research on wheatgrass establishes its anticancer and antioxidant potential. Current work was focused to determine antileukemic effect of wheat grass.MATERIALS AND METHODS: The commercial wheatgrass powder was extracted with 95% of methanol. Methanol extract of wheat grass was studied for acute oral toxicity as per revised Organization for Economic Cooperation and Development Guidelines number 423. Leukemia was successfully induced in Wister rats by intravenous injection of benzene. The blood was collected and analyzed for hematological parameters. Phagocytotic activity of the extract was determined.RESULTS: Phytochemical screening revealed the presence of flavonoids, phenolics, carbohydrates, and amino acids. From acute toxicity studies, it was found that the methanol extract of wheatgrass was safe up to a dose level of 2000 mg/kg of body weight. Outcomes of hematological parameters in various experimental groups of murine model demonstrated antileukemic effect of extract. Methanol extract of wheatgrass aroused the process of phagocytosis of killed Candida albicans and also demonstrated a significant chemotactic activity at all tested concentrations.CONCLUSION: In the current work, methanol extract of wheat grass demonstrated antileukemic potential that might be due to the presence of flavonoids and polyphenolics in it. Further isolation, structural characterization of active constituents is necessary to extrapolate the mechanism of action.

Indian J Pharmacol. 2015 Jul-Aug;47(4):394-7. PMID: 26288471


Cocoa may be a potential agent in the prevention and treatment of colitis-associated cancer.

Patients with inflammatory bowel disease (IBD) are at increased risk for developing ulcerative colitis-associated colorectal cancer (CRC). The interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT)-3 signaling regulates survival and proliferation of intestinal epithelial cells and play an important role in the pathogenesis of IBD and CRC. Cocoa is enriched with polyphenols that known to possess antioxidant, anti-inflammatory and antitumor activities. Here, we explored the antitumor effects and mechanisms of cocoa diet on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium model, with a particular focus on whether cocoa exerts its anticancer effect through the IL-6/STAT3 pathway. We found that cocoa significantly decreased the tumor incidence and size in CAC-induced mice. In addition to inhibiting proliferation of tumor epithelial cells, cocoa suppressed colonic IL-6 expression and subsequently activation of STAT3. Thus, our findings demonstrated that cocoa diet suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation. In addition, cocoa induces apoptosis by increased the expressions of Bax and caspase 3 and decreased Bcl-xl. Thus, we conclude that cocoa may be a potential agent in the prevention and treatment of CAC.

J Nutr Biochem. 2015 Aug 10. Epub 2015 Aug 10. PMID: 26355019


Brazilian red propolis treatment attenuated hypertension and structural renal damage in a renal ablation model.

The pathogenic role of inflammation and oxidative stress in chronic kidney disease (CKD) is well known. Anti-inflammatories and antioxidant drugs has demonstrated significant renoprotection in experimental nephropathies. Moreover, the inclusion of natural antioxidants derived from food and herbal extracts (such as polyphenols, curcumin and lycopene) as an adjuvant therapy for slowing CKD progression has been largely tested. Brazilian propolis is a honeybee product, whose anti-inflammatory, antimicrobial and antioxidant effects have been widely shown in models of sepsis, cancer, skin irritation and liver fibrosis. Furthermore, previous studies demonstrated that this compound promotes vasodilation and reduces hypertension. However, potential renoprotective effects of propolis in CKD have never been investigated. The aim of this study was to evaluate the effects of a subtype of Brazilian propolis, the Red Propolis (RP), in the 5/6 renal ablation model (Nx). Adult male Wistar rats underwent Nx and were divided into untreated (Nx) and RP-treated (Nx+RP) groups, after 30 days of surgery; when rats already exhibited marked hypertension and proteinuria. Animals were observed for 90 days from the surgery day, when Nx+RP group showed significant reduction of hypertension, proteinuria, serum creatinine retention, glomerulosclerosis, renal macrophage infiltration and oxidative stress, compared to age-matched untreated Nx rats, which worsened progressively over time. In conclusion, RP treatment attenuated hypertension and structural renal damage in Nx model. Reduction of renal inflammation and oxidative stress could be a plausible mechanism to explain this renoprotection.

PLoS One. 2015 ;10(1):e0116535. Epub 2015 Jan 21. PMID: 25607548


Consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia

Grape skin and seeds contain large amounts of phytochemicals such as polyphenols, resveratrol, and proanthocyanidins, which possess antioxidant activities. Cisplatin is widely used in the treatment of cancer. High doses of cisplatin have also been known to produce acute adverse effects. The aim of this study was to investigate the protective effects of antioxidant properties of whole grape juice (with skin and seeds) on cisplatin-induced acute gastrointestinal tract disorders and nephrotoxicity in Wistar rats. Gastric emptying is significantly increased in whole grape juice-pretreated rats when compared to cisplatin treatment alone. The expression of ghrelin mRNA of stomach is increased in rats with whole grape juice. However, pretreatment with whole grape juice did not reduce renal function markers in acute renal toxicity. No significant changes were recorded in the oxidative stress/antioxidant status parameters of any study group. In contrast, pretreatment with whole grape juice slightly improved tubular cell vacuolization, tubular dilatation, and cast formation in renal tubules. These results show that consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia but does not offer protection against cisplatin-induced acute renal toxicity.

Hum Exp Toxicol. 2015 Oct 1. Epub 2015 Oct 1. PMID: 26429932


dietary polyphenols play a significant role in the prevention of degenerative diseases via the improvement in colonic environment without any absorption from digestive tract.

The effects of dietary polyphenols on human health have mainly been discussed in the context of preventing degenerative diseases, particularly cardiovascular diseases and cancer. The antioxidant properties of polyphenols have been widely studied, but it has become clear that the mechanism of action of polyphenols extends beyond the modulation of oxidative stress, as they are poorly absorbed from the digestive tract. The purpose of this study was to clarify the effects of polyphenols on the colonic environment, intestinal barrier function, and gut microbiota. We demonstrated that dietary polyphenols derived from aronia, haskap, and bilberry, markedly elevated the amount of fecal mucin and immunoglobulin A (IgA) as an intestinal barrier function and ameliorated the disturbance in gut microbiota caused by a high fat diet in rats. These results suggest that dietary polyphenols play a significant role in the prevention of degenerative diseases through improvement of the colonic environment without any absorption from the digestive tract.

J Clin Biochem Nutr. 2015 Nov ;57(3):212-6. Epub 2015 Sep 29. PMID: 26566306


Curcumin could protect against the vascular side effects of methotrexate by preventing an increase in oxidative stress.

Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effectswere comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.

Can J Physiol Pharmacol. 2015 Nov 16:1-8. Epub 2015 Nov 16. PMID: 26571019


Pterostilbene decreases the antioxidant defenses of aggressive cancer cells in vivo

AIMS: Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies lack of correlation to the bioavailable concentrations is a critical issue. Some reports had suggested that these molecules down-regulate the stress response, which may affect growth and the antioxidant protection of malignant cells. Initially we studied this potential underlying mechanism using different human melanomas (with genetic backgrounds correlating with most melanomas), growing in nude mice as xenografts, and pterostilbene (Pter, a natural dimethoxylated analog of resveratrol).RESULTS: Intravenous administration of Pter decreased human melanoma growth in vivo. However Pter, at levels measured within the tumors, did not affect melanoma growth in vitro. Pter inhibited pituitary production of the adrenocorticotropin hormone (ACTH), decreased plasma levels of corticosterone and, thereby, down regulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent antioxidant defense system in growing melanomas. Exogenous corticosterone or genetically-induced Nrf2 overexpression in melanoma cells prevented the inhibition of tumor growth and decreased antioxidant defenses in these malignant cells. These effects and mechanisms were also found in mice bearing different human pancreatic cancers. Glutathione depletion (selected as an anti-melanoma strategy) facilitated the complete elimination by chemotherapy of melanoma cells isolated from mice treated with Pter.INNOVATION: Although bioavailability-related limitations may preclude direct anticancer effects in vivo, natural polyphenols may also interfere with the growth and defense of cancer cells by down-regulating the pituitary gland-dependent ACTH synthesis.CONCLUSIONS: Pter down-regulates glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells.

Antioxid Redox Signal. 2015 Dec 9. Epub 2015 Dec 9. PMID: 26651028


6-Gingerol is a potent inducer of p53 reactivation in HPV positive cervical cancer cells through proteasome inhibition.

Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer.

Oncotarget. 2015 Nov 25. Epub 2015 Nov 25. PMID: 26621832


Seaweed polyphenols may inhibit pancreatic cancer relapse/recurrence by targeting therapy-orchestrated stem-cell signaling in residual cells.

INTRODUCTION: Therapy-associated onset of stemness-maintenance in surviving tumor-cells dictates tumor relapse/recurrence. Recently, we recognized the anti-pancreatic cancer (PC) potential of seaweed polyphenol manifolds and narrowed down three superior drug-deliverables that could serve as adjuvants and benefit PC cure. Utilizing the PC- cancer stem cells (PC-CSCs) grown ex vivo and mouse model of residual-PC, we investigated the benefits of seaweed polyphenols in regulating stemness-maintenance.METHODS: ALDH(+)CD44(+)CD24(+) PC-CSCs from Panc-1, Panc-3.27, MiaPaCa-2, or BxPC-3 cells-derived xenografts grown ex vivo were either mock-irradiated, exposed to fractionated irradiation (FIR, 2Gy/D for 5 days), treated with polyphenols (100 μg/ml) of Hormophysa triquerta (HT-EA), Spatoglossum asperum (SA-EA) or Padina tetrastromatica (PT-EA) with/without FIR were examined for cell viability, transcription of 93 stem-cell-related molecules (QPCR profiling). Polyphenol-dependent regulation of FIR-transactivated Oct4, Zic3, EIF4C, Nanog, and LIF (QPCR) and functional translation of Nanog, SOX2, and OCT3/4 (immunoblotting) were examined in Panc-1/Panc-3.27/MiaPaCa-2/BxPC-3-xenografts derived PC-CSCs. Effect of seaweed-polyphenols in the regulation of EMT (N-Cadherin), pluripotency- (SOX2, OCT3/4, Nanog) and stemness-maintenance (PI3KR1, LIF, CD44) in therapy (FIR, 2Gy/D for 5D/wk for 3-weeks) resistant residual tumors were examined by tissue microarray construction and automated immunohistochemistry.RESULTS: Ex vivo exposure of PC-CSCs to SA-EA, PT-EA and HT-EA exhibit dose-dependent inhibition of cell viability. FIR amplified the transcription of 69, 80, 74 and 77 stem-cell related genes in MiaPaCa-2-, Panc-1-, Panc-3.27- and BXPC3-established xenograft-derived ALDH(+)CD44(+)CD24(+)PC-CSCs. Treatment with SA-EA, PT-EA, or HT-EA completely suppressed FIR-activated stem-cell transcriptional machinery in ALDH(+)CD44(+)CD24(+)PC-CSCs established from MiaPaCa-2, Panc-1, Panc-3.27 and BXPC3 xenografts. QPCR validated EIF4C, OCT3/4, Nanog, LIF, and ZIC3 transcriptional profile outcomes. Nanog, Sox2, and OCT3/4 immunoblotting affirmed the PC-CSC radiosensitizing benefit of seaweed polyphenols. Residual-PC tissues microarrayed and immunostained after in vivo treatments recognized complete regulation of FIR-induced SOX2, OCT3/4, Nanog, LIF, CD44, PIK3R1, N-Cadherin, and E-Cadherin with SA-EA, PT-EA, and HT-EA.CONCLUSIONS: These data, for the first time, documented the EMT/stemness-maintenance in therapy-resistant PC-CSCs. Further, the data suggest that seaweed polyphenols may inhibit PC relapse/recurrence by targeting therapy-orchestrated stem-cell signaling in residual cells.

Stem Cell Res Ther. 2015 ;6(1):182. Epub 2015 Sep 22. PMID: 26395574


Green tea, red wine and lemon extracts reduce experimental tumor growth and cancer drug toxicity.

AIM: To evaluate antitumor effect of plant polyphenol extracts from green tea, red wine lees and/or lemon peel alone and in combination with antitumor drugs on the growth of different transplanted tumors in experimental animals.MATERIALS AND METHODS: Green tea extract (GTE) was prepared from green tea infusion. GTE-based composites of red wine (GTRW), lemon peel (GTRWL) and/or NanoGTE as well as corresponding nanocomposites were prepared. The total polyphenolics of the different GTE-based extracts ranged from 18.0% to 21.3%. The effects of GTE-based extracts were studied in sarcoma 180, Ehrlich carcinoma, B16 melanoma, Ca755 mammary carcinoma, P388 leukemia, L1210 leukemia, and Guerin carcinoma (original, cisplatin-resistant and doxorubicin-resistant variants). The extracts were administered as 0.1% solution in drinking water (0.6-1.0 mg by total polyphenolics per mouse per day and 4.0-6.3 mg per rat per day).RESULTS: Tumor growth inhibition (TGI) in mice treated with NanoGTE, cisplatin or cisplatin + NanoGTE was 27%, 55% and 78%, respectively, in Sarcoma 180%, 21%, 45% and 59%, respectively, in Ehrlich carcinoma; and 8%, 13% and 38%, respectively in B16 melanoma. Composites of NanoGTE, red wine, and lemon peel (NanoGTRWL) enhanced the antitumor effects of cyclophosphamide in mice with Ca755 mammary carcinoma. The treatment with combination of NanoGTE and inhibitors of polyamines (PA) synthesis (DFMO + MGBG) resulted in significant TGI of P388 leukemia (up to 71%) and L1210 leukemia. In rats transplanted with Guerin carcinoma (parental strain), treatment with GTRW or GTE alone resulted in 25-28% TGI vs. 55-68% TGI in cisplatin-treated animals. The inhibition observed in the case of combination of GTE or GTRW with cisplatin was additive giving 81-88% TGI. Similar effects were observed when combinations of the cytostatics with GTE (or NanoGTE) were tested against cisplatin- or doxorubicin-resistant Guerin carcinoma. Moreover, the plant extracts lowered side toxicity of the drugs. Treatment with GTE, NanoGTE, and NanoGTRW decreased the levels of malondialdehyde in heart, kidney and liver tissue of experimental animals, as well as the levels of urea and creatinine in blood serum, increased erythrocyte and platelet counts, hemoglobin content, and decreased leucocyte counts.CONCLUSION: The obtained data indicate the prospects for further development of GTE and corresponding nanocomposites as auxiliary agents in cancer chemotherapy.

Exp Oncol. 2015 Dec ;37(4):262-71. PMID: 26710838


Eruca sativa seed extract may be considered a promising natural product against breast cancer.

The effect of Eruca sativa seed extract (SE) on nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels was investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(α)anthracene (DMBA). DMBA increased NF-κB, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while, decreased glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. After DMBA administration, SE treatment reduced NF-κB, COX-2 and Bcl-2 gene expression levels and LP. Hence, SE treatment reduced inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC. Analysis revealed that SE has high concentrations of total flavonoids, triterpenoids, alkaloids and polyphenolic compounds such as gallic, chlorogenic, caffeic, 3,4-dicaffeoyl quinic, 3,5-dicaffeoyl quinic, tannic, cinnamic acids, catechin and phloridzin. These findings indicate that SE may be considered a promising natural product from cruciferous vegetables against breast cancer, especially given its high antioxidant properties.

Asian Pac J Cancer Prev. 2015 ;16(18):8411-8. PMID: 26745094


Polyphenol enrichment of a blueberry preparation by fermentation increases its chemopreventive potential.

BACKGROUND: Naturally occurring polyphenolic compounds from fruits, particularly from blueberries, have been reported to be significantly involved in cancer chemoprevention and chemotherapy. Biotransformation of blueberry juice by Serratia vaccinii increases its polyphenolic content and endows it with anti-inflammatory properties.METHODS: This study evaluated the effect of a polyphenol-enriched blueberry preparation (PEBP) and its non-fermented counterpart (NBJ), on mammary cancer stem cell (CSC) development in in vitro, in vivo and ex vivo settings. Effects of PEBP on cell proliferation, mobility, invasion, and mammosphere formation were measured in vitro in three cell lines: murine 4T1 and human MCF7 and MDA-MB-231. Ex vivo mammosphere formation, tumor growth and metastasis observations were carried out in a BALB/c mouse model.RESULTS: Our research revealed that PEBP influence cellular signaling cascades of breast CSCs, regulating the activity of transcription factors and, consequently, inhibiting tumor growth in vivo by decreasing metastasis and controlling PI3K/AKT, MAPK/ERK, and STAT3 pathways, central nodes in CSC inflammatory signaling. PEBP significantly inhibited cell proliferation of 4T1, MCF-7 and MDA-MB-231. In all cell lines, PEBP reduced mammosphere formation, cell mobility and cell migration. In vivo, PEBP significantly reduced tumor development, inhibited the formation of ex vivo mammospheres, and significantly reduced lung metastasis.CONCLUSIONS: This study showed that polyphenol enrichment of a blueberry preparation by fermentation increases its chemopreventive potential by protecting mice against tumor development, inhibiting the formation of cancer stem cells and reducing lung metastasis. Thus, PEBP may represent a novel complementary alternative medicine therapy and a source for novel therapeutic agents against breast cancer.

J Transl Med. 2016 ;14(1):13. Epub 2016 Jan 14. PMID: 26762586


Resveratrol attenuates liver fibrosis via the Akt/NF-κB pathways.

Liver fibrosis is a wound-healing response to chronic liver injury that results in the accumulation of extracellular matrix proteins. It eventually leads to cirrhosis of the liver and liver failure, and it is a critical threat to the health and lives of patients with chronic liver diseases. No effective treatment is currently available. Resveratrol is a polyphenol with antioxidant, anti‑cancer and anti‑inflammatory properties. It has been reported that resveratrol prevents liver fibrosis, possibly by inhibiting NF‑κB activation. The present study investigated the mechanisms by which resveratrol prevented liver fibrosis, focusing on the possible involvement of the NF‑κB pathway. Mice with carbon tetrachloride (CCl4)‑induced liver fibrosis were treated with various concentrations of resveratrol. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and tumor necrosis factor (TNF)‑α were detected by ELISAs. Expression of α‑smooth muscle actin (α‑SMA), collagen I, inhibitor of NF‑κB (IκB) and NF‑κB were detected by western blot analysis. In addition, the present study examined the effects of resveratrol on the expression of fibrosis markers in LX‑2 cells. Western blot analysis was further used to detect the levels of Akt and phosphorylated Akt, as well as the nuclear levels of IκB, phosphorylated IκB and NF‑κB p65. The expression of α‑SMA in resveratrol‑treated LX‑2 cells was detected by immunofluorescence and flow cytometry, which demonstrated that resveratrol decreased the expression of α‑SMAin LX‑2 cells. Resveratrol also decreased CCl4‑induced upregulation of serum AST, ALT, TNF‑α, α‑SMA and collagen I. Finally, resveratrol prevented the activation of NF‑κB and Akt. The results of the present study therefore indicated that resveratrol attenuates liver fibrosis via the Akt/NF-κB pathways.

Mol Med Rep. 2016 Jan ;13(1):224-30. Epub 2015 Nov 2. PMID: 26530037


Curcumin not only inhibits tumor angiogenesis, but also suppresses the production of VEGF in response to hypoxia.

Curcumin, a natural polyphenol compound from the perennial herb Curcuma longa, has been proved to be beneficial for tumor-bearing animals through inhibiting tumor neovasculature formation, but the underlying mechanisms are unclear. Here, we aim to test whether curcumin affects VEGF-VEGFR2 signaling pathway and attenuates defective hematopoiesis induced by VEGF in tumor model. We demonstrated that curcumin inhibited proliferation, migration of HUVEC under VEGF stimulation and caused HUVEC apoptosis, and blocked VEGFR2 activation and its downstream signaling pathways in vitro. Furthermore, in VEGF over-expressing tumor model, curcumin significantly inhibited the tumor growth accelerated by VEGF in a dose-dependent manner and improved anemia and extramedullary hematopoiesis in livers and spleens of tumor-bearing mice induced by tumor-derived VEGF. Immunohistochemical analysis showed that curcumin normalized vasculature structures of livers and reduced tumor microvessel density. ELISA revealed that curcumin suppressed VEGF secretion from tumor cells both in vitro and in vivo. Survival analysis showed that curcumin significantly improved survival ability of VEGF tumor-bearing mice. Taken together, these findings establish curcumin as a modulator of VEGF and VEGF-VEGFR2 signaling pathway, with potential implication for improving the quality of life of cancer patients.

Oncotarget. 2015 Aug 14 ;6(23):19469-82. PMID: 26254223


A strawberry extract had effective hypoglycemic activity against alloxan induced hyperglycemia in albino rats.

The strawberries (Fragaria x ananassa) of Rosaceae family are an accomplished source of bioactive compounds such as ascorbic acid and diverse range of polyphenols including anthocyanins, phenolic acids, flavonols, ellagitannins etc. These phenolic compounds classify strawberry as an important health promoting food. Strawberries are proved to have potent antioxidant capacity in various in vitro assay systems. The in vivo beneficial effects are getting explored against various ailments including cancer, metabolic syndrome, and cardiovascular diseases. The present research study was designed to analyze the effect of strawberry fruit extracts (water and methanol) against alloxan induced hyperglycemia in albino rats of Wister strain. Upon alloxan (150mg/kg body weight) induction, the diabetic animals showed marked increase in the values of plasma glucose, urea, uric acid, creatinine and concomitant decrease in body weight and plasma insulin level. The oral administration of strawberry extracts for 45 days in diabetic animals reversed the biochemical changes significantly (P0.05) to near normal. Furthermore, the restoration of body weight loss was also observed. The results suggest that the strawberry extract has effective hypoglycemic activity against alloxan diabetes. The poly phenolic antioxidant contents of the strawberry fruit extracts are responsible for the observed biological effect.

Pak J Pharm Sci. 2016 Jan ;29(1):255-60. PMID: 26826817


Extracts rich in gallo- and ellagitannins act on different molecular targets in the protection against ulcerative colitis.

SCOPE: Tannin-rich fruits have been evaluated as alternative prevention strategies for colorectal cancer based on their anti-inflammatory properties. This study compared tannin-rich preparations from mango (rich in gallotannins) and pomegranate (rich in ellagitannins) in the dextran sodium sulfate-induced colitis model.METHODS AND RESULTS: In rats, mango and pomegranate beverages decreased intestinal inflammation and the levels of pro-inflammatory cytokines in mucosa and serum. The mango beverage suppressed the ratio of phosphorylated/total protein expression of the IGF-1R-AKT/mTOR axis and down-regulated mRNA expression of Igf1, Insr, and pik3cv. Pomegranate decreased p70S6K and RPS6, as well as Rps6ka2, Map2k2, and Mapk1 mRNA. In silico modeling indicated a high binding-docked of gallic acid to the catalytic domain of IGF-1R, which may suppress the activity of the enzyme. Ellagic acid docked effectively into the catalytic domains of both IGF-1R and EGFR. In vitro assays with lipopolysaccharide-treated CCD-18Co cells using polyphenolic extracts from each beverage, as well as pure compounds, corroborated the predictions made in silico.CONCLUSION: Mango polyphenols inhibited the IGF-1R- AKT/mTOR axis, and pomegranate polyphenols downregulate the mTOR downstream pathway through reductions in ERK1/2. These results suggest that extracts rich in gallo- and ellagitannins act on different molecular targets in the protection against ulcerative colitis. This article is protected by copyright. All rights reserved.

Mol Nutr Food Res. 2016 Mar 29. Epub 2016 Mar 29. PMID: 27028006


EGCG modulates the reversal of gene silencing involved in colon carcinogenesis.

Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis. In colon cancer, RXRα, an important dimerization partner with other nuclear transcription factors, is silenced through this mechanism. We previously found that colon tumors in ApcMin/+ mice had diminished levels of RXRα protein and expression levels of this gene were restored by treatment with a green tea intervention, due to reduced promoter methylation of RXRα. We hypothesized that CIMP+ cell lines, which epigenetically silence key regulatory genes would also evidence silencing of RXRα and EGCG treatment would restore its expression. We indeed found EGCG to restore RXRα activity levels in the human cell lines, in a dose dependent manner and reduced RXRα promoter methylation. EGCG induced methylation changes in several other colon cancer related genes but did not cause a decrease in global methylation. Numerous epidemiological reports have shown the benefits of green tea consumption in reducing coloncancer risk but to date no studies have shown that the risk reduction may be related to the epigenetic restoration by tea polyphenols. Our results show that EGCG modulates the reversal of gene silencing involved in colon carcinogenesis providing a possible avenue for colon cancer prevention and treatment.

Oncotarget. 2016 May 6. Epub 2016 May 6. PMID: 27167203


Green tea and quercetin could enhance the therapeutic effect of Doc in a less-toxic manner.

BACKGROUND: Chemotherapy with docetaxel (Doc) remains the standard treatment for metastatic and castration-resistance prostate cancer (CRPC). However, the clinical success of Doc is limited by its chemoresistance and side effects. This study investigated whether natural products green tea (GT) and quercetin (Q) enhance the therapeutic efficacy of Doc in CRPC in mouse models.METHODS: Male severe combined immunodeficiency (SCID) mice (n = 10 per group) were inoculated with androgen-independent prostate cancer PC-3 cells subcutaneously. When tumors were established the intervention started. Mice were administered with GT + Q, Doc 5 mg/kg (LD), GT + Q + LD Doc, Doc 10 mg/kg (HD) or control. The concentration of GTpolyphenols in brewed tea administered as drinking water was 0.07 % and Q was supplemented in diet at 0.4 %. Doc was intravenously injected weekly for 4 weeks, GT and Q given throughout the study.RESULTS: GT + Q or LD Doc slightly inhibited tumor growth compared to control. However, the combination of GT and Q with LD Doc significantly enhanced the potency of Doc 2-fold and reduced tumor growth by 62 % compared to LD Doc in 7-weeks intervention. A decrease of Ki67 and increase of cleaved caspase 7were observed in tumors by the mixture, along with lowered blood concentrations of growth factors like VEGF and EGF. The mixture significantly elevated the levels of tumor suppressor mir15a and mir330 in tumor tissues. An increased risk of liver toxicity was only observed with HD Doc treatment.CONCLUSIONS: These results provide a promising regimen to enhance the therapeutic effect of Doc in a less toxic manner.

J Exp Clin Cancer Res. 2016 ;35(1):73. Epub 2016 May 6. PMID: 27151407


Eastern prickly pear extract may be a promising candidate for treating human cervical carcinoma.

In this study, we found that the total polyphenol and ascorbic acid levels in the fruit of Opuntia humifusa are higher than those in other parts of the plant. We further hypothesized that antioxidants in O. humifusa might affect the growth or survival of cancer cells. Hexane extracts of seeds and ethyl acetate extracts of fruits and stems significantly suppressed the proliferation of HeLa cervical carcinoma cells, but did not affect the proliferation of normal human BJ fibroblasts. Additionally, the extracts of O. humifusa induced G1 phase arrest in HeLa cells. The O. humifusa extracts reduced the levels of G1 phase-associated cyclin D1, cyclin-dependent kinase 4 (Cdk4), and phosphorylated retinoblastoma proteins. Moreover, p21(WAF1/Cip1) and p53 expression significantly increased after treatment. We examined the effects of ethyl acetate extracts of O. humifusa fruit (OHF) on HeLa cells xenograft tumor growth. OHF treatment significantly reduced tumor volume and this decrease was correlated with decreased Cdk4 and cyclin D1 expression. Furthermore, flavonoids, trans Taxifolin, and dihydrokaempferol, were isolated from OHF. Thus, this extract may be a promising candidate for treating human cervical carcinoma.

J Med Food. 2015 Jan ;18(1):31-44. PMID: 25379883


EGCG significantly inhibited gastric tumour growth in vivo by inhibiting Wnt/β-catenin signalling.

(-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, could affect carcinogenesis and development of many cancers. However, the effects and underlying mechanisms of EGCG on gastric cancer remain unclear. We found that EGCG significantly inhibited proliferation and increased apoptosis of SGC-7901 cells in vitro. The decreased expressions of p-β-catenin(Ser552), p-GSK3β(S9) and β-catenin target genes were detected in SGC-7901 cells after treated by EGCG. XAV939 and β-catenin plasmid were further used to demonstrate the inhibition of EGCG on canonical Wnt/β-catenin signalling. Moreover, EGCG significantly inhibited gastric tumour growth in vivo by inhibiting Wnt/β-catenin signalling. Taken together, our findings establish that EGCG suppressed gastric cancer cell proliferation and demonstrate that this inhibitory effect is related to canonical Wnt/β-catenin signalling. This study raises a new insight into gastric cancer prevention and therapy, and provides evidence that green tea could be used as a nutraceutical beverage.

Int J Food Sci Nutr. 2016 Jun 24:1-10. Epub 2016 Jun 24. PMID: 27338284


Administration of quercetin at 15mg/kg body weight resulted in a ~70% reduction in tumor growth.

The Akt/adenosine monophosphate protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway has emerged as a critical signaling nexus for regulating cellular metabolism, energy homeostasis, and cell growth. Thus, dysregulation of this pathway contributes to the development of metabolic disorders such as obesity, type 2diabetes, and cancer. We previously reported that a combination of grape polyphenols (resveratrol, quercetin and catechin: RQC), at equimolar concentrations, reduces breast cancer (BC) growth and metastasis in nude mice, and inhibits Akt and mTOR activities and activates AMPK, an endogenous inhibitor of mTOR, in metastatic BC cells. The objective of the present study was to determine the contribution of individual polyphenols to the effect of combined RQC on mTOR signaling. Metastatic BC cells were treated with RQC individually or in combination, at various concentrations, and the activities (phosphorylation) of AMPK, Akt, and the mTOR downstream effectors, p70S6 kinase (p70S6K) and 4E binding protein (4EBP1), were determined by Western blot. Results show that quercetin was the most effective compound for Akt/mTOR inhibition. Treatment with quercetin at 15μM had a similar effect as the RQC combination in the inhibition of BC cell proliferation, apoptosis, and migration. However, cell cycle analysis showed that the RQC treatment arrested BC cells in the G1 phase, while quercetin arrested the cell cycle in G2/M. In vivo experiments, using SCID mice with implanted tumors from metastatic BC cells, demonstrated that administration of quercetin at 15mg/kg body weight resulted in a ~70% reduction in tumor growth. In conclusion, quercetin appears to be a viable grape polyphenol for future development as an anti BC therapeutic.

PLoS One. 2016 ;11(6):e0157251. Epub 2016 Jun 10. PMID: 27285995


Continuous exposure of pancreatic cancer cells to dietary bioactive agents does not induce drug resistance unlike chemotherapy.

The repeated treatment of cancer cells with chemo- or radiotherapy induces therapy resistance, but it was previously unknown whether the same effect occurs upon continuous exposure of cancer cells to diet-derived chemopreventive agents. We elucidated this interesting question in pancreatic ductal adenocarcinoma, which is a highly aggressive cancer entity with a marked resistance toward gemcitabine and other cytotoxic drugs. The isothiocyanate sulforaphane, present in cruciferous vegetables, and the polyphenol quercetin, present in many fruits and vegetables induced apoptosis and reduced viability in gemcitabine-sensitive BxPC-3 cells but not in non-malignant ductal pancreas cells and mesenchymal stromal cells. In turn, BxPC-3 cells were treated with increasing concentrations of gemcitabine, sulforaphane or quercetin for more than 1 year and the surviving subclones Bx-GEM, Bx-SF and Bx-Q were selected, respectively. While Bx-GEM cells acquired a total resistance, Bx-SF or Bx-Q cells largely kept their sensitivity as proved by MTT assay, annexin staining and FACS analysis. The evaluation of the self-renewal-, differentiation- and migration-potential by colony formation, differentiation or migration assays demonstrated that cancer stem cell features were enriched in gemcitabine-resistant cells, but decreased in sulforaphane- and quercetin-long time-treated cells. These results were confirmed by orthotopic xenotransplantation of cancer cells to the mouse pancreas, where Bx-GEM formed large, Bx-Q small and Bx-SF cells almost undetectable tumors. An mRNA expression profiling array and subsequent gene set enrichment analysis and qRT-PCR confirmed that tumor progression markers were enriched in Bx-GEM, but reduced in Bx-SF and Bx-Q cells. This study demonstrates that the continuous exposure of pancreatic cancer cells to sulforaphane or quercetin does not induce resistance in surviving cells but reduces tumorigenicity by inhibition of tumor progression markers. These results highlight that cancer cells may not adapt to the preventive and therapeutic effects of a regular fruit- and vegetable-based diet.

Cell Death Dis. 2016 ;7(6):e2246. Epub 2016 Jun 2. PMID: 27253410


ECG may be used as an anti-invasion agent for the adjuvant treatment and metastasis control of human lung cancer cells.

Epithelial-to-mesenchymal transition (EMT) and invasion potential have been considered as essential factors in cancer metastasis, which is the major cause of cancer death. EMT is a multi-step process that involves gain invasion, cytoskeleton change, cell adhesion, and proteolytic extracellular matrix degradation. Epicatechin-3-gallate (ECG), which is a natural polyphenolic component of green tea, elicits several antioxidant and anti-inflammatory effects. However, the effects of ECG on cancer invasion and EMT of human lung carcinoma remain unknown. We provided molecular evidence supporting the anti-metastatic effect of ECG. This compound suppressed the invasion (P < 0.001) of highly metastatic A549 cells by reducing the activities of matrix metalloproteinase-2 (P < 0.001) and urokinasetype plasminogen activator (P < 0.001). ECG also reversed the transforming growth factor (TGF)-β1-induced EMT and upregulated epithelial markers, such as E-cadherin. Conversely, ECG inhibited mesenchymal markers, such as fibronectin and p-FAK. The subcutaneous inoculation of this compound also inhibited the tumor growth of theA549 cells in vivo. Therefore, ECG may be used as an anti-cancer and anti-invasion agent for the adjuvant treatment and metastasis control of human lung cancer cells. ECG may also be administered as an effective chemopreventive agent against TGF-β1-induced EMT.

Food Chem Toxicol. 2016 Aug ;94:1-10. Epub 2016 May 17. PMID: 27224248


Intra-tumoral injection of TriCurin significantly inhibited tumor growth by 85.5%.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV-positive HNSCC) has rapidly increased over the past 30 years prompting the suggestion that an epidemic may be on the horizon. Therefore, there is a clinical need to develop alternate therapeutic strategies to manage the growing number of HPV-positive HNSCC patients. TriCurin is a composition of three food-derived polyphenols in unique stoichiometric proportions consisting of curcumin from the spice turmeric, resveratrol from red grapes, and epicatechin gallate from green tea. Cell viability, clonogenic survival, and tumorsphere formation were inhibited and significant apoptosis was induced by TriCurin in UMSCC47 and UPCI:SCC090 HPV-positive HNSCC cells. Moreover, TriCurin decreased HPV16E6 and HPV16E7 and increased p53 levels. In a pre-clinical animal model of HPV-positive HNSCC, intra-tumoral injection of TriCurin significantly inhibited tumor growth by 85.5% compared to vehicle group (P

Oncotarget. 2016 Jul 16. Epub 2016 Jul 16. PMID: 27437871


This research confirms the potential role of resveratrol in the treatment of renal diseases.

Obesity-related renal diseases have been a worldwide issue. Effective strategy that prevents high fat-diet induced renal damage is of great significance. Resveratrol, a natural plant polyphenol, is famous for its antioxidant activity, cardioprotective effects and anticancer properties. However whether resveratrol can play a role in the treatment of renal diseases is unknown. In this study, we added resveratrol in normal glucose or high glucose medium and provide evidences that resveratrol protects against high-glucose triggered oxidative stress and cell senescence. Moreover, mice were fed with standard diet, standard diet plus resveratrol, high-fat diet or high-fat diet plus resveratrol for 3 months, and results show that resveratrol treatment prevents high-fat diet induced renal pathological damage by activating SIRT1, a key member in the mammalian sirtuin family that response to calorie restriction life-extension method. This research confirms the potential role of resveratrol in the treatment of renal diseases and may provide an effective and convenient method to mimic the beneficial effects of calorie restriction.

Biol Pharm Bull. 2016 ;39(9):1448-54. PMID: 27582325


Ingestion of pomegranate polyphenols is associated with inhibition of x-ray-induced genomic instability and elevated GSH.

Ionizing radiation (IR) is a well-documented human carcinogen. The increased use of IR in medical procedures has doubled the annual radiation dose and may increase cancer risk. Genomic instability is an intermediate lesion in IR-induced cancer. We examined whether pomegranate extract (PE) suppresses genomic instability induced by x-rays. Mice were treated orally with PE and exposed to an x-ray dose of 2 Gy. PE intake suppressed x-ray-induced DNA double-strand breaks (DSBs) in peripheral blood and chromosomal damage in bone marrow. We hypothesized that PE-mediated protection against x-ray-induced damage may be due to the upregulation of DSB repair and antioxidant enzymes and/or increase in glutathione (GSH) levels. We found that expression of DSB repair genes was not altered (Nbs1 and Rad50) or was reduced (Mre11, DNA-PKcs, Ku80, Rad51, Rad52 and Brca2) in the liver of PE-treated mice. Likewise, mRNA levels of antioxidant enzymes were reduced (Gpx1, Cat, and Sod2) or were not altered (HO-1 and Sod1) as a function of PE treatment. In contrast, PE-treated mice with and without IR exposure displayed higher hepatic GSH concentrations than controls. Thus, ingestion of pomegranate polyphenols is associated with inhibition of x-ray-induced genomic instability and elevated GSH, which may reduce cancer risk.

Nutr Cancer. 2016 Sep 27:1-8. Epub 2016 Aug 27. PMID: 27673354


Quercetin and resveratrol incorporated in liposomes may be of value in the treatment of pre-cancerous and cancerous skin lesions.

The present investigation reports the development of liposomes for the co-delivery of naturally occurring polyphenols, namely quercetin and resveratrol. Small, spherical, uni/bilamellar vesicles were produced, as demonstrated by light scattering, cryo-TEM, SAXS. The incorporation of quercetin and resveratrol in liposomes did not affect their intrinsic antioxidant activity, as DPPH radical was almost completely inhibited. The cellular uptake of the polyphenols was higher when they were formulated in liposomes, and especially when co-loaded rather than as single agents, which resulted in a superior ability to scavenge ROS in fibroblasts. The in vivo efficacy of the polyphenols in liposomes was assessed in a mouse model of skin lesion. The topical administration of liposomes led to a remarkable amelioration of the tissue damage, with a significant reduction of oedema and leukocyte infiltration. Therefore, the proposed approach based on polyphenol vesicular formulation may be of value in the treatment of inflammation/oxidative stress associated with pre-cancerous/cancerous skin lesions.

Int J Pharm. 2016 Nov 20 ;513(1-2):153-163. Epub 2016 Aug 5. PMID: 27609664


Treatment with mulberry leaf extract partially protected the livers of rats from NDEA-induced hepatocarcinogenesis.

BACKGROUND/AIM: The leaves of white mulberry (Morus alba L.) contain various polyphenolic compounds possessing strong antioxidant activity and anticancer potential. This study was designed to investigate the chemopreventive effect of aqueous extract of mulberry leaves against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis.MATERIALS AND METHODS: Wistar rats were divided into four groups: control, mulberry extract-treated, NDEA-treated, and mulberry extract plus NDEA-treated. Mulberry extract was given in the diet (1,000 mg/kg b.w./day); NDEA was given in drinking water.RESULTS: Mulberry extract reduced the incidence of hepatocellular carcinoma, dysplastic nodules, lipid peroxidation, protein carbonyl formation, and DNA degradation. Treatment with mulberry leaf extract along with NDEA challenge did not affect the activity of antioxidant enzymes and glutathione content.CONCLUSION: Treatment with mulberry leaf extract partially protected the livers of rats from NDEA-induced hepatocarcinogenesis and a direct antioxidant mechanism appears to contribute to its anticarcinogenic activity.

In Vivo. 2016 11-12;30(6):807-812. PMID: 27815465


These results suggest that ellagic acid may have a potential role as an adjunct therapy for bladder cancer.

Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.

Nutrients. 2016 Nov 22 ;8(11). Epub 2016 Nov 22. PMID: 27879653


Mango polyphenols and their major microbial metabolite, pyrogallol, inhibit proliferation of breast cancer cells.

The objective of this study was to assess the underlying mechanisms of mango polyphenol decreased cell proliferation and tumor volume in ductal carcinoma in situ breast cancer. We hypothesized that mango polyphenols suppress signaling along the AKT/mTOR axis while up-regulating AMPK. To test this hypothesis, mango polyphenols (0.8 mg gallic acid equivalents per day) and pyrogallol (0.2 mg/day) were administered for 4 weeks to mice xenografted with cells subcutaneously (n=10 per group). Tumor volumes were significantly decreased, both mango and pyrogallol groups displayed greater than 50% decreased volume compared to control. There was a significant reduction of phosphorylated protein levels of IR, IRS1, IGF-1R, and mTOR by mango; while pyrogallol significantly reduced the phosphorylation levels of IR, IRS1, IGF-1R, p70S6K, and ERK. The protein levels of Sestrin2, which is involved in AMPK-signaling, were significantly elevated in both groups. Also, mango significantly elevated AMPK phosphorylation and pyrogallol significantly elevated LKB1 protein levels. In an in vitro model, mango and pyrogallol increased reactive oxygen species (ROS) generation and arrested cells in S phase. In silico modeling indicates that pyrogallol has the potential to bind directly to the allosteric binding site of AMPK, inducing activation. When AMPK expression was down-regulated using siRNA in vitro, pyrogallol reversed the reduced expression of AMPK. This indicates that pyrogallol not only activates AMPK, but also increases constitutive protein expression. These results suggest that mango polyphenols and their major microbial metabolite, pyrogallol, inhibit proliferation of breast cancer cells through ROS-dependent up-regulation of AMPK and down-regulation of the AKT/mTOR pathway.

J Nutr Biochem. 2016 Nov 15 ;41:12-19. Epub 2016 Nov 15. PMID: 27951515


Co-administration of EGCG and doxorubicin has potential as a feasible strategy to mitigate the drugs cardiotoxicity.

AIMS: (-)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol compound, plays an important role in the prevention of cardiovascular disease and cancer. The present study aimed to investigate the effects of EGCG on doxorubicin (DOX)-induced cardiotoxicity in Sarcoma 180 (S180) tumor-bearing mice.MAIN METHODS: S180 tumor-bearing mice were established by subcutaneous inoculation of S180 cells attached to the axillary region. The extent of myocardial injury was accessed by the amount of lactate dehydrogenase (LDH) released in serum. Heart tissue was morphologically studied with transmission electron microscopy. Apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔѰm) as well as calcium concentration were measured by flow cytometric analysis. Expression levels of manganese superoxide dismutase (MnSOD) were analyzed by Western blot.KEY FINDINGS: Results showed that the combination with EGCG and DOX significantly inhibited tumor growth and enhanced induction of apoptosis compared with DOX alone. Moreover, administration of EGCG could suppress DOX-induced cardiotoxicity as evidenced by alleviating LDH release and apoptosis in cardiomyocyte. EGCG-evoked cardioprotection was in association with the increase ofΔѰm and MnSOD expression. EGCG was also found to attenuate ROS generation and myocardial calcium overload in Sarcoma 180 tumor-bearing mice subjected to DOX.SIGNIFICANCE: EGCG alleviated DOX-induced cardiotoxicity possibly in part mediated by increasing of MnSOD andѰm, reducing myocardial calcium overload and subsequently attenuating the apoptosis and LDH release. Our findings suggest that co-administration of EGCG and DOX have potential as a feasible strategy to mitigate cardiotoxicity of DOX without compromising its chemotherapeutic value.

Life Sci. 2016 Dec 9. Epub 2016 Dec 9. PMID: 27956351


Pterostilbene attenuates early brain injury following subarachnoid hemorrhage.

Pterostilbene (PTE), one of the polyphenols present in plants such as blueberries and grapes, has been suggested to have various effects, such as anti-oxidation, anti-apoptosis, and anti-cancer effects. Subarachnoid hemorrhage (SAH) is a severe neurological event known for its high morbidity and mortality. Recently, early brain injury (EBI) has been reported to play a significant role in the prognosis of patients with SAH. The present study aimed to investigate whether PTE could attenuate EBI after SAH was induced in C57BL/6 J mice. We also studied possible underlying mechanisms. After PTE treatment, the neurological score and brain water content of the mice were assessed. Oxidative stress and neuronal injury were also evaluated. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3) inflammasome activity was assessed using western blot analysis. Our results indicated that PTE treatment reduces the SAH grade, neurological score, and brain water content following SAH. PTE treatment also reduced NLRP3 inflammasome activation. PTE alleviated the oxidative stress following SAH as evidenced by the dihydroethidium staining, superoxide dismutase activity, malondialdehyde content, 3-nitrotyrosie and 8-hydroxy-2-deoxyguanosine levels, and gp91(phox) and 4-hydroxynonenal expression levels. Additionally, PTE treatment reduced neuronal apoptosis. In conclusion, our study suggests that PTE attenuates EBI following SAH possibly via the inhibition of NLRP3 inflammasome and Nox2-related oxidative stress.

Mol Neurobiol. 2016 Sep 24. Epub 2016 Sep 24. PMID: 27665283


EGCG inhibited SW780 bladder cancer tumor growth by down-regulation of NF-κB and MMP-9.

Epigallocatechin-3-gallate (EGCG), the bioactive polyphenol in green tea, has been demonstrated to have various biological activities. Our study aims to investigate the antiproliferation and antimigration effects of EGCG against bladder cancer SW780 cells both in vitro and in vivo. Our results showed that treatment of EGCG resulted in significant inhibition of cell proliferation by induction of apoptosis, without obvious toxicity to normal bladder epithelium SV-HUC-1 cells. EGCG also inhibited SW780 cell migration and invasion at 25-100μM. Western blot confirmed that EGCG induced apoptosis in SW780 cells by activation of caspases-8, -9 and -3, Bax, Bcl-2 and PARP. Besides, animal study demonstrated that EGCG [100 mg/kg, intraperitoneal (i.p.) injection daily for 3 weeks] decreased the tumor volume significantly in mice bearing SW780 tumors, as well as the tumor weight (decreased by 68.4%). In addition, EGCG down-regulated the expression of nuclear factor-kappa B (NF-κB) and matrix metalloproteinase (MMP)-9 in both protein and mRNA level in tumor and SW780 cells. When NF-κB was inhibited, EGCG showed no obvious effect in cell proliferation and migration. In conclusion, our study demonstrated that EGCG was effective in inhibition SW780 cell proliferation and migration, and presented first evidence that EGCG inhibited SW780 tumor growth by down-regulation of NF-κB and MMP-9.

J Nutr Biochem. 2016 Dec 20 ;41:56-64. Epub 2016 Dec 20. PMID: 28040581


Rutin attenuates doxorubicin-induced cardiotoxicity.

Doxorubicin as anticancer agent can cause dose-dependent cardiotoxicity and heart failure in the long term. Rutin as a polyphenolic flavonoid has been illustrated to protect hearts from diverse cardiovascular diseases. Its function is known to be related to its antioxidant and antiinflammatory activity which may regulate multiple cellular signal pathways. However, the role of rutin on doxorubicin-induced cardiotoxicity has yet to be discovered. In this study, we explored the protective role of rutin on doxorubicin-induced heart failure and elucidated the potential mechanisms of protective effects of rutin against cardiomyocyte death. We analyzed cardiac tissues at the time point of 8weeks after doxorubicin treatment. The results by echocardiography, TUNEL staining, Masson's trichrome staining as well as Western blot analysis revealed that doxorubicin induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were alleviated by rutin treatment. Western blot analysis indicated that the underlying mechanisms included inhibition excessive autophagy and apoptosis mediated by Akt activation. Collectively, our findings suggest that suppression of autophagy and apoptosis by administration of rutin could attenuate doxorubicin-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating this devastating side effect induced by doxorubicin. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren&Megan Yingmei Zhang.

Biochim Biophys Acta. 2017 Jan 6. Epub 2017 Jan 6. PMID: 28069395


A polyphenol-rich strawberry extract exerts important biological activities against a highly invasive breast cancer cell line.

We describe the biological effects of a polyphenol-rich strawberry extract (PRSE), obtained from the"Alba"variety, on the highly aggressive and invasive basal-like breast cancer cell line A17. Dose-response and time-course experiments showed that PRSE is able to decrease the cellular viability of A17 cells in a time- and dose-dependent manner. PRSE effect on cell survival was investigated in other tumor and normal cell lines of both mouse and human origin, demonstrating that PRSE is more active against breast cancer cells. Cytofluorimetric analysis of A17 cells demonstrated that sub-lethal doses of PRSE reduce the number of cells in S phase, inducing the accumulation of cells in G1 phase of cell cycle. In addition, the migration of A17 cells was studied monitoring the ability of PRSE to inhibit cellular mobility. Gene expression analysis revealed the modulation of 12 genes playing different roles in the cellular migration, adhesion and invasion processes. Finally, in vivo experiments showed the growth inhibition of A17 cells orthotopically transplanted into FVB syngeneic mice fed with PRSE. Overall, we demonstrated that PRSE exerts important biological activities against a highly invasive breast cancer cell line both in vitro and in vivo suggesting the strawberry extracts as preventive/curative food strategy.

Sci Rep. 2016 Aug 8 ;6:30917. Epub 2016 Aug 8. PMID: 27498973


Oligonol may act as an anti-aging molecule by modulating SIRT1/autophagy/AMPK pathways.

BACKGROUND/OBJECTIVES: Oligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined.MATERIALS/METHODS: In this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans.RESULTS: Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of SIRT1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae.CONCLUSIONS: These data demonstrated that oligonol may act as an anti-aging molecule by modulating SIRT1/autophagy/AMPK pathways.

Nutr Res Pract. 2016 Feb ;10(1):3-10. Epub 2016 Jan 8. PMID: 26865910


EGCG inhibits arsenic-induced inflammation and apoptosis through suppression of oxidative stress in mice.

BACKGROUND/AIMS: Exposure to arsenic in individuals has been found to be associated with various health-related problems including skin lesions, cancer, and cardiovascular and immunological disorders. (-)-Epigallocatechin-3-gallate (EGCG), the main and active polyphenolic catechin present in green tea, has shown potent antioxidant, anti-apoptotic and anti-inflammatory activity in vivo and in vitro. Thus, the present study was conducted to investigate the protective effects of EGCG against arsenic-induced inflammation and immunotoxicity in mice.METHODS: Serum IL-1β, IL-6 and TNF-α were determined by ELISA, tissue catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), nitric oxide and caspase 3 by commercial kits, mitochondrial membrane potential with Rh 123, mitochondrial ROS with 2',7'-dichlorofluorescin diacetate (DCFH-DA), apoptotic and necrotic cells and T-cell phenotyping with Flow cytometry analysis.RESULTS: The results showed that arsenic treatment significantly increased oxidative stress levels (as indicated by catalase, malonyldialdehyde, superoxide dismutase, glutathione and reactive oxygen species), increased levels of inflammatory cytokines and promoted apoptosis. Arsenic exposure increased the relative frequency of the CD8+(Tc) cell subpopulation (from 2.8 to 18.9%) and decreased the frequency of CD4+(Th) cells (from 5.2 to 2.7%). Arsenic exposure also significantly decreased the frequency of T(CD3) (from 32.5% to 19.2%) and B(CD19) cells (from 55.1 to 32.5%). All of these effects induced by NaAsO2 were attenuated by EGCG.CONCLUSIONS: The present in vitro findings indicate that EGCG attenuates not only NaAsO2-induced immunosuppression but also inflammation and apoptosis.

Cell Physiol Biochem. 2017 Apr 3 ;41(5):1788-1800. Epub 2017 Apr 3. PMID: 28365685


Polyphenols from oleaster leaves might have a strong potential as chemopreventive agent in colorectal cancer.

Dietary polyphenols, derived from natural products, have received a great interest for their chemopreventive properties against cancer. In this study, we investigated the effects of phenolic extract of the oleaster leaves (PEOL) on tumor growth in mouse model and on cell death in colon cancer cell lines. We assessed the effect of oleaster leaf infusion on HCT116 (human colon cancer cell line) xenograft growth in athymic nude mice. We observed that oleaster leaf polyphenol-rich infusion limited HCT116 tumor growth in vivo. Investigations of PEOL on two human CRC cell lines showed that PEOL induced apoptosis in HCT116 and HCT8 cells. We demonstrated an activation of caspase-3, -7 and -9 by PEOL and that pre-treatment with the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), prevented PEOL-induced cell death. We observed an involvement of the mitochondrial pathway in PEOL-induced apoptosis evidenced by reactive oxygen species (ROS) production, a decrease of mitochondrial membrane potential, and cytochrome c release. Increase in intracellular Ca2+ concentration induced by PEOL represents the early event involved in mitochondrial dysfunction, ROS-induced endoplasmic reticulum (ER) stress and apoptosis induced by PEOL, as ruthenium red, an inhibitor of mitochondrial calcium uptake inhibited apoptotic effect of PEOL, BAPTA/AM inhibited PEOL-induced ROS generation and finally, N-acetyl-L-cysteine reversed ER stress and apoptotic effect of PEOL. These results demonstrate that polyphenols from oleaster leaves might have a strong potential as chemopreventive agent in colorectal cancer.

PLoS One. 2017 ;12(2):e0170823. Epub 2017 Feb 17. PMID: 28212423


Resveratrol can elicit neuroprotective effects on rotenone-induced parkinsonism.

The aim of the present study was to investigate whether resveratrol could reduce nigral iron levels to prevent the degeneration of dopaminergic neurons in the substantia nigra (SN) of C57BL/6 mice induced by rotenone. Parkinson's disease (PD) is an age-related neurodegenerative disorder; elevated iron levels in the SN participate in neuronal death in PD. Resveratrol is a kind of polyphenolic compounds and possess antioxidant, anticancer, and anti-inflammatory biological functions. Although many research groups have investigated the neuroprotective effects of resveratrol against PD, the precise mechanisms underlying its beneficial effects on dopaminergic neuron are poorly defined. In this study, rotenone-treated mice were used to examine neuroprotective roles of resveratrol in PD. Sixty-four adult C57BL/6 mice were divided into four groups: vehicle control mice, rotenone mice, resveratrol-treated rotenone mice, resveratrol mice. In the present study, we found that chronic administration of rotenone significantly induced motor coordination impairment and increased iron levels and dopaminergic neuron loss in SN in mice. Resveratrol administration significantly protected mice from rotenone-induced motor coordination impairment, elevated iron levels, and dopaminergic neuronal loss. Our results show that resveratrol can elicit neuroprotective effects on rotenone-induced parkinsonism through reducing nigral iron levels.

Neuroreport. 2017 May 3. Epub 2017 May 3. PMID: 28471847


Resveratrol may confer multi-organ protection against cyclophosphamide toxicity via antioxidant and anti-inflammatory mechanisms.

CONTEXT: Cyclophosphamide (CyP), an efficient anticancer drug, may damage normal human cells. Resveratrol (RES), a natural polyphenol, has a diverse pharmacological properties.OBJECTIVE: To test possible protective effect of RES on multi-organ damage caused by CyP.MATERIALS AND METHODS: RES (10 mg/kg/day) was administered orally for 8 days. In independent rat groups, CyP toxicity was induced via a single dose of 150 mg/kg i.p. 3 days before the end of experiment, with or without RES treatment.RESULTS: Compared to control, CyP caused significant increase in organ-to-body weight ratios of heart, kidney and liver, with deterioration in their functional parameters; namely serum creatine kinase, blood urea nitrogen, creatinine, alanine aminotransferase and aspartate aminotransferase. CyP also caused distortion in these organs' histology, with significant tissue oxidative stress, manifested by decrease in reduced glutathione and catalase, as well as increase in malondialdehyde and nitric oxide levels. Furthermore, CyP caused multi-organ inflammatory effects as shown by increased tumor necrosis factor-α levels, as well as up-regulation of nuclear factor-κB expressions. Using RES concurrently with CyP restored heart, kidney and liver functional parameters, as well as their normal histology. RES also reversed oxidative stress, as well as inflammatory signs caused by CyP alone.CONCLUSIONS: RES may be beneficial adjuvant that confers multi-organ protection against CyP toxicity via antioxidant and anti-inflammatory mechanisms.

Immunopharmacol Immunotoxicol. 2017 May 2:1-8. Epub 2017 May 2. PMID: 28463035


Mulberry cyanidin-3-glucoside-induced apoptosis in breast cancer cells.

Fruits of Morus alba L. (mulberry) have various bioactive compounds such as polyphenols and anthocyanins and used as a herbal medicine. However, the anti-cancer effects and molecular basis have not been elucidated. We examined the effect of the cyanidin-3-glucoside isolated from mulberry by acidified-methanol extraction on MDA-MB-453 human breast cancer cells. The results showed that treatment with the mulberry C3G increased cell death in a dose-dependent manner with alteration of apoptotic protein contents, and DNA fragmentation, suggesting that cells undergo apoptosis. Supporting the observations, treatment with the cyanidin-3-glucoside showed active apoptosis by caspase-3 cleavage and DNA fragmentation through Bcl-2 and Bax pathway. Indeed, cyanidin-3-glucoside inhibited tumor growth in MDA-MB-453 cells-inoculated nude mice. Tumor growth of xenograft nude mouse was reduced compared with the control group by the cyanidin-3-glucoside. These results show that mulberry cyanidin-3-glucoside inhibit the proliferation and growth in the in vitro and in vivo models. These data suggest that mulberry cyanidin-3-glucoside-induced apoptosis in breast cancer cells (MDA-MB-453), which has a potential to perform as an anti-cancer agent.

Anticancer Agents Med Chem. 2017 Mar 27. Epub 2017 Mar 27. PMID: 28356020


Oral administration of apple procyanidins inhibits the proliferation of tumor cells by inducing apoptosis through the intrinsic mitochondrial pathway.

Various epidemiologic and experimental in vivo and in vitro studies have suggested that polyphenols derived from fruits, vegetables and beverages might decrease the risk of developing lifestyle diseases, such as cardiovascular disorders and cancer. Apples are a major dietary source of polyphenols. Here we investigated the antitumor activity of apple polyphenols (APs) and procyanidins, namely condensed tannins, both in vitro and in vivo studies. APs and procyanidins inhibited the growth of transplanted B16 mouse melanoma cells and BALB-MC.E12 mouse mammary tumor cells, and increased the survival rate of the host mice-transplanted B16 cells. Among the APs, the apple procyanidins specifically, rather than other polyphenols such as chlorogenic acid, (-)-epicatechin, phloridzin and procyanidin B2, had a major effect on cell proliferation and induced apoptosis in vitro. The apple procyanidins increased mitochondrial membrane permeability and cytochrome c release from mitochondria and activated caspase-3 and caspase-9 within the tumor cells. In addition, we separated eight procyanidin fractions according to the degree of polymerization using normal-phase chromatography, and detected strong anti-tumor activity in the procyanidin pentamer and higher degree fractions. Our results indicate that the oral administration of apple procyanidins inhibits the proliferation of tumor cells by inducing apoptosis through the intrinsic mitochondrial pathway.

Carcinogenesis. 2008 Mar ;29(3):585-93. Epub 2007 Sep 7. PMID: 17827407


Curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition.

Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60-550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition.

Thromb Haemost. 2015 Feb ;113(2):319-28. Epub 2014 Sep 18. PMID: 25230992


Kaempferol might act as a therapeutic potential candidate for cancer metastasis.

Matrix metalloproteinases (MMPs) have been regarded as major critical molecules assisting tumor cells during metastasis, for excessive ECM (ECM) degradation, and cancer cell invasion. In the present study, in vitro and in vivo assays were employed to examine the inhibitory effects of kaempferol, a natural polyphenol of flavonoid family, on tumor metastasis. Data showed that kaempferol could inhibit adhesion, migration, and invasion of MDA-MB-231 human breast carcinoma cells. Moreover, kaempferol led to the reduced activity and expression of MMP-2 and MMP-9, which were detected by gelatin zymography, real-time PCR, and western blot analysis, respectively. Further elucidation of the mechanism revealed that kaempferol treatment inhibited the activation of transcription factor activator protein-1 (AP-1) and MAPK signaling pathway. Moreover, kaempferol repressed phorbol-12-myristate-13-acetate (PMA)-induced MMP-9 expression and activity through suppressing the translocation of protein kinase Cδ (PKCδ) and MAPK signaling pathway. Our results also indicated that kaempferol could block the lung metastasis of B16F10 murine melanoma cells as well as the expression of MMP-9 in vivo. Taken together, these results demonstrated that kaempferol could inhibit cancer cell invasion through blockingthe PKCδ/MAPK/AP-1 cascade and subsequent MMP-9 expression and its activity. Therefore, kaempferol might act as a therapeutic potential candidate for cancer metastasis.

Biochem Cell Biol. 2015 Feb ;93(1):16-27. Epub 2014 Sep 12. PMID: 25453494


Encapsulation of EGCG in transferrin-bearing vesicles is a promising therapeutic strategy.

AIM: The therapeutic potential of epigallocatechin-3-gallate (EGCG), a green tea polyphenol with anticancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study was to determine whether a tumor-targeted vesicular formulation of EGCG would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo.MATERIALS & METHODS: Transferrin-bearing vesicles encapsulating EGCG were administered intravenously to mice bearing subcutaneous A431 and B16-F10 tumors.RESULTS: The intravenous administration of EGCG encapsulated in transferrin-bearing vesicles resulted in tumor suppression in 40% of A431 and B16-F10 tumors. Animal survival was improved by more than 20 days compared with controls.CONCLUSION: Encapsulation of EGCG in transferrin-bearing vesicles is a promising therapeutic strategy.

Nanomedicine (Lond). 2013 Feb ;8(2):181-92. Epub 2012 Aug 14. PMID: 22891867


Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers.

Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

Oncol Lett. 2016 Dec ;12(6):4975-4982. Epub 2016 Nov 2. PMID: 28105204


Coupling to a cancer cell-specific antibody potentiates tumoricidal properties of curcumin.

In vitro studies have shown that curcumin, a polyphenol from the culinary component turmeric, has strong anticancer properties. However, there is no consensus on its therapeutic effect in human. Our earlier experiments involving implanted murine melanoma B16F10 cells in the neck or brain of syngeneic C57BL6 mice showed that tail vein injection of curcumin blocks formation of lesions and tumor in these mice. However, such treatment was ineffective in eliminating established tumors that already occupied≤10% of brain volume. Possible reasons include low solubility and rapid metabolism of curcumin in vivo. To increase its efficacy, we have linked curcumin through a cleavable arm to an antibody (Ab) against the melanoma surface antigen Muc18. The antibody-coupled curcumin was 230-fold more effective in eliminating B16F10 cells in vitro, and in vivo, it rapidly decimated established, B16F10-evoked brain tumors, enabling the rescued mice to live normally far beyond 90 days from implantation of cancer cells. In contrast, mice treated with Muc18 Ab alone died of brain tumor within a month. In B16F10 cells, curcumin-Ab (adduct) treatment caused a dramatic inhibition of NF-kB: a transcription factor that is constitutively activated in cancer cells. Furthermore, overexpression of NF-kB in the B16F10 cells blocked adduct-evoked stimulation of caspase-3/7 activity. Thus, by suppressing NF-kB, the curcumin adduct inhibits other downstream tumor-promoting proteins, thereby eliminating the B16F10 cells. Our study submits a novel yet generally applicable strategy of converting curcumin into a potent anticancer agent and provides a mechanistic framework for its action.

Int J Cancer. 2012 Aug 15 ;131(4):E569-78. Epub 2012 Jan 3. PMID: 21989768


Green tea prevents non-melanoma skin cancer by enhancing DNA repair.

Excessive exposure of the skin to solar ultraviolet (UV) radiation is one of the major factors for the development of skin cancers, including non-melanoma. For the last several centuries the consumption of dietary phytochemicals has been linked to numerous health benefits including the photoprotection of the skin. Green tea has been consumed as a popular beverage world-wide and skin photoprotection by green tea polyphenols (GTPs) has been widely investigated. In this article, we have discussed the recent investigations and mechanistic studies which define the potential efficacy of GTPs on the prevention of non-melanoma skin cancer. UV-induced DNA damage, particularly the formation of cyclobutane pyrimidine dimers, has been implicated in immunosuppression and initiation of skin cancer. Topical application or oral administration of green tea through drinking water of mice prevents UVB-induced skin tumor development, and this prevention is mediated, at least in part, through rapid repair of DNA. The DNA repair by GTPs is mediated through the induction of interleukin (IL)-12 which has been shown to have DNA repair ability. The new mechanistic investigations support and explain the anti-photocarcinogenic activity, in particular anti-non-melanoma skin cancer, of green tea and explain the benefits of green tea for human health.

Arch Biochem Biophys. 2011 Apr 15 ;508(2):152-8. Epub 2010 Nov 19. PMID: 21094124


Kaempferol can safely inhibit the metastasis of the 786-O RCC cells into the lungs by about 87.4%.

Kaempferol, which is isolated from several natural plants, is a polyphenol belonging to the subgroup of flavonoids. Kaempferol exhibits various pharmacological activities, including anti-inflammatory, antioxidant, antimicrobial, and anticancer activities. In this study, kaempferol can significantly inhibit the invasion and migration of 786-O renal cell carcinoma (RCC) without cytotoxicity. We examined the potential mechanisms underlying its anti-invasive activities on 786-O RCC cells. Western blot was performed, and the results showed that kaempferol attenuates the manifestation of metalloproteinase-2 (MMP-2) protein and activity. The inhibitive effect of kaempferol on MMP-2 may be attributed to the downregulation of phosphorylation of Akt and focal adhesion kinase (FAK). By examining the SCID mice model, we found that kaempferol can safely inhibit the metastasis of the 786-O RCC cells into the lungs by about 87.4% as compared to vehicle treated control animals. In addition, the lung tumor masses of mice pretreated with 2-10 mg/kg kaempferol were reduced about twofold to fourfold. These data suggested that kaempferol can play a promising role in tumor prevention and cancer metastasis inhibition.

Int J Med Sci. 2017 ;14(10):984-993. Epub 2017 Aug 18. PMID: 28924370


Pomegranate by-products could be used in colorectal cancer chemoprevention.

SCOPE: To investigate the effect of pomegranate mesocarp, a polyphenol-rich by-product of juice production, in colorectal cancer (CRC) chemoprevention.METHODS AND RESULTS: A mesocarp decoction (PMD) was administered for 6 weeks in the diet to Pirc rats, mutated in Apc, a key-gene in CRC. Mucin Depleted Foci (MDFs), as CRC biomarkers, were reduced in PMD-fed rats compared to Controls (MDF/colon: 34±4 vs 47±3, P = 0.02). Apoptosis in MDFs from PMD-treated rats was increased compared to Controls (2.5±0.2 vs 1.6±0.2, P

Mol Nutr Food Res. 2017 Sep 25. Epub 2017 Sep 25. PMID: 28948694


Ocimum sanctum has protective effects against smoke induced lung and neuronal tissue damage in rats.

Smoke induced oxidative stress is known to cause various cancers and associated health problems including lung cancer. Herbal extracts have been reported as antioxidant supplements which attenuate free radical induced oxidative damage of tissues, among which Ocimum sanctum has been reported as the elixir of life due to its innumerable health benefits. In the present study, we investigated the protective effect of O. sanctum against cracker smoke induced lung and brain tissue damage. The results of the study demonstrate that O. sanctum regulates the hematological and serum biochemical parameters such as RBC, WBC, blood urea nitrogen and creatinine kinase. O. sanctum supplementation inhibited oxidative stress as analyzed by SOD, CAT enzyme levels and i-NOS, HSP-70 protein expression. O. sanctum administration also regulated neurotransmitter levels, such as serotonin, dopamine, and regulated acetylcholine esterase levels which play a vital role in neuronal function. Further O. sanctum treatment also preserved the morphology of lung and brain tissues of smoke stress induced rats as observed by histopathology and transmission electron microscope analysis. The biodistribution of O. sanctum was showed its accumulation in key tissues such as kidney, liver, lungs and heart. The LC-ESI-MS/MS analysis of O. sanctum showed the presence of polyphenols, flavonoids and fatty acids which might be responsible for the observed anti-stress effects.

Biomed Pharmacother. 2017 Jul ;91:1-12. Epub 2017 Apr 20. PMID: 28433747


EGCG may be useful as an adjuvant therapy for bronchial asthma.

Asthma is a chronic disease associated with hyperresponsiveness, obstruction and remodeling of the airways. Epithelial-mesenchymal transition (EMT) has an important role in these alterations and may account for the accumulation of subepithelial mesenchymal cells, thus contributing to airway hyperresponsiveness and remodeling. Epigallo-catechin‑3‑gallate (EGCG), which is a type of polyphenol, is the most potent ingredient in green tea, and exhibits antibacterial, antiviral, antioxidative, anticancer and chemopreventive activities. Recently, numerous studies have investigated the protective effects of EGCG against asthma and other lung diseases. In the present study, the role of EGCG in ovalbumin (OVA)‑challenged asthmatic mice was determined. In addition, the inhibitory effects of EGCG against transforming growth factor (TGF)‑β1‑induced EMT and migration of 16HBE cells, and the underlying mechanisms of the phosphatidylinositol 3‑kinase/protein kinase B (PI3K/Akt) signaling pathway, were investigated by immunofluorescence, Transwell, wound healing assay and western blot analysis, respectively. The results indicated that EGCG may suppress inflammation and inflammatory cell infiltration into the lungs of OVA‑challenged asthmatic mice, and may also inhibit EMT via the PI3K/Akt signaling pathway throughupregulating the expression of phosphatase and tensin homolog (PTEN) in vivo and in vitro. The present study also revealed the anti‑migratory effects of EGCG in TGF‑β1‑induced 16HBE cells, thus suggesting it may reduce airway remodeling. The present study provides a novel insight into understanding the protective effects of EGCG on airway remodeling in asthma, and indicates that EGCG may be useful as an adjuvant therapy for bronchial asthma.

Int J Mol Med. 2017 Nov 28. Epub 2017 Nov 28. PMID: 29207033


Apple extracts can extend cellular lifespan by lowering the level of intracellular ROS and by the activation of cellular signalling pathways.

BACKGROUND: During the past years, a number of studies have demonstrated the positive effect of apple on ageing and different diseases such as cancer, degenerative and cardiovascular diseases. The unicellular yeast Saccharomyces cerevisiae represents a simple eukaryotic model to study the effects of different compounds on lifespan. We previously demonstrated that apple extracts have anti-ageing effects in this organism because of their antioxidant properties. In particular, the effect is related to the presence in this fruit of polyphenols, which give a large contribution to the antioxidant activity of apples.METHODS: We we used a clonogenic assay to assess the viability and the resistance to oxidative stress of S. cerevisiae cells in the presence of Annurca apple extracts. The production of ROS and the aberrant morphology of nuclei were detected by cell staining with the fluorescent dies Dihydrorhodamine 123 and DAPI, respectively. Mitochondrial morphology was analyzed by following the localization of the mito-GFP protein into the mitochondrial matrix.RESULTS: In this study, we show that apple extracts can increase yeast lifespan, reduce the levels of reactive oxygen species and cell sensitivity to oxidative stress, and prevent nuclei and mitochondria fragmentation protecting cells from regulated cell death.CONCLUSIONS: In this paper, by using the yeast S. cerevisiae as a model, we have demonstrated that Annurca extracts possess antioxidant properties thanks to which the extracts can reduce the intracellular ROS levels and have anti-apoptotic functions thus prolonging cell lifespan. These results contribute to knowledge on the effects of natural compounds on ageing and support the use of yeast as a model organism for the development of simple tests to assess the effectiveness of bioactive substances from natural sources.

BMC Complement Altern Med. 2017 Apr 5 ;17(1):200. Epub 2017 Apr 5. PMID: 28381226


Pomegranate juice supplementation significantly decreased the incidence of lung cancer.

Background: Cigarette smoke (CS) induces an oxidative stress, DNA damage, and lung cancer. Pomegranate juice (PJ) possess potent antioxidant activity attributed to its polyphenols. We investigated whether PJ supplementation would prevent the formation of lung nodules, attenuate mitotic activity, and reduce hypoxia-inducible factor-1α (HIF-1α) expression secondary to CS exposure in an animal model.Methods: Mice were divided into: Control group, CS group, CS + PJ group, and PJ-only group. CS and CS + PJ were exposed to CS, 5 days per week, for a total of 5 months. Animals were then housed for additional four months. CS + PJ and PJ groups received PJ throughout the experiment period while others received placebo. At the end of the experiment, the incidence of lung nodules was assessed by (1) histological analysis, (2) mitotic activity [measurement of PHH3 antibodies], and (3) measurement of HIF-1α expression.Results: The incidence of lung nodules was significantly increased in CS. CS exposure significantly increased PHH3 and HIF-1α expression. PJ supplementation attenuated the formation of lung nodules and reduced PHH3 and HIF-1α expression.Conclusion: PJ supplementation significantly decreased the incidence of lung cancer, secondary to CS, prevented the formation of lung nodules, and reduced mitotic activity and HIF-1α expression in an animal model.

Oxid Med Cell Longev. 2017 ;2017:6063201. Epub 2017 Nov 30. PMID: 29333211


The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation.

Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. Glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells. Interestingly, we found that Ph (10-150 μM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB-231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10-150 μM, for 24 h) significantlydecreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (α-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstratedin vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues. In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis.

J Food Drug Anal. 2018 Jan ;26(1):221-231. Epub 2017 Apr 18. PMID: 29389559


Black Tea inhibits lung carcinogenesis.

One of the most promising strategies for cancer prevention is chemoprevention by daily used food and beverages. Black tea, the most widely consumed beverage, is a source of compounds with antioxidative, antimicrobial, antimutagenic and anticarcinogenic properties. Lung cancer is the most common cause of cancer deaths in both men and women worldwide. Over one million people around the world are likely to be killed by lung cancer due to increased tobacco smoking and environmental pollutants, especially car exhausts. Therefore chemopreventive intervention using black tea and its active components may be a viable means to reduce lung cancer death. In the present investigation, we used benzo(a)pyrene (BP) to induce lung carcinogenesis in mice for the assessment of potential apoptosis-inducing and proliferation-suppressing effects of theaflavins and epigallocatechin gallate, active components of black tea. Hyperplasia, dysplasia and carcinoma in situ evident in the carcinogen control group on the 8th, 17th and 26th weeks respectively, were effectively reduced after treatment with theaflavins and epigallocatechin gallate. Significant reduction in number of proliferating cells and increased number of apoptotic cells was also found on the 8th, 17th and 26th week of treatment with theaflavins and epigallocatechin gallate in BP-exposed mice. Our observation suggests a promising role for black tea polyphenols in the prevention of lung cancer.

Eur J Cancer Prev. 2005 Jun;14(3):215-21. PMID: 15901989


Blueberry can inhibit colon cancer cell proliferation and induce cell death.

Research has shown that diets rich in phenolic compounds may be associated with lower risks of several chronic diseases including cancer. This study systematically evaluated the bioactivities of phenolic compounds in rabbiteye blueberries and assessed their potential antiproliferation and apoptosis induction effects using two colon cancer cell lines, HT-29 and Caco-2. Polyphenols in three blueberry cultivars, Briteblue, Tifblue, and Powderblue, were extracted and freeze-dried. The extracts were further separated into phenolic acids, tannins, flavonols, and anthocyanins using an HLB cartridge and LH20 column. Some individual phenolic acids and flavonoids were identified by HPLC with >90% purity in anthocyanin fractions. The dried extracts and fractions were added to the cell culture medium to test for antiproliferation activities and induction of apoptosis. Flavonol and tannin fractions resulted in 50% inhibition of cell proliferation at concentrations of 70-100 and 50-100 microg/mL in HT-29 and Caco-2 cells, respectively. The phenolic acid fraction showed relatively lower bioactivities with 50% inhibition at approximately 1000 microg/mL. The greatest antiproliferation effect among all four fractions was from the anthocyanin fractions. Both HT-29 and Caco-2 cell growth was significantly inhibited by >50% by the anthocyanin fractions at concentrations of 15-50 microg/mL. Anthocyanin fractions also resulted in 2-7 times increases in DNA fragmentation, indicating the induction of apoptosis. The effective dosage levels are close to the reported range of anthocyanin concentrations in rat plasma. These findings suggest that blueberry intake may reduce colon cancer risk.

Mol Cell Biochem. 2008 May;312(1-2):139-45. Epub 2008 Mar 10.v PMID: 16131149


Curcumin (from Turmeric) inhibits autoimmune diseases.

The immune system has evolved to protect the host from microbial infection; nevertheless, a breakdown in the immune system often results in infection, cancer, and autoimmune diseases. Multiple sclerosis, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, myocarditis, thyroiditis, uveitis, systemic lupus erythromatosis, and myasthenia gravis are organ-specific autoimmune diseases that afflict more than 5% of the population worldwide. Although the etiology is not known and a cure is still wanting, the use of herbal and dietary supplements is on the rise in patients with autoimmune diseases, mainly because they are effective, inexpensive, and relatively safe. Curcumin is a polyphenolic compound isolated from the rhizome of the plant Curcuma longa that has traditionally been used for pain and wound-healing. Recent studies have shown that curcumin ameliorates multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease in human or animal models. Curcumin inhibits these autoimmune diseases by regulating inflammatory cytokines such as IL-1beta, IL-6, IL-12, TNF-alpha and IFN-gamma and associated JAK-STAT, AP-1, and NF-kappaB signaling pathways in immune cells. Although the beneficial effects of nutraceuticals are traditionally achieved through dietary consumption at low levels for long periods of time, the use of purified active compounds such as curcumin at higher doses for therapeutic purposes needs extreme caution. A precise understanding of effective dose, safe regiment, and mechanism of action is required for the use of curcumin in the treatment of human autoimmune diseases.

Adv Exp Med Biol. 2007;595:425-51. PMID: 17569223


Green Tea induces apoptosis in drug-resistant small-cell lung carcinoma.

Epidemiological studies on humans and investigations in animal models suggest that consumption of green tea has anti-cancer effects. Small-cell lung carcinoma (SCLC) has a poor prognosis, particularly due to the development of drug resistance. We investigated the effects of the green tea polyphenol, epigallocatechin-3-gallate (EGCG) on human SCLC cells. EGCG had similar effects (IC(50) of approximately 70 microM) on drug-sensitive (H69) and drug-resistant (H69VP) SCLC cells, indicating that it is not part of the drug resistance phenotype expressed in these cells. In both cell lines, incubation in EGCG at 1 x IC(50) for 24h resulted in 50-60% reduced telomerase activity as measured by a PCR-based assay for telomeric repeats. Colorimetric assays of cells treated for 36 h with EGCG demonstrated a reduction in activities of caspases 3 (50%) and 9 (70%) but not caspase 8, indicating initiation of apoptosis. DNA fragmentation as measured by ELISA occurred within cells treated with EGCG and this was confirmed by TUNEL staining. Flow cytometric analysis of SCLC cells incubated for 36 h in EGCG indicated a cell-cycle block in S phase. These data indicate the potential use of EGCG, and possibly green tea, in treating SCLC.  

Biochem Biophys Res Commun. 2007 Aug 17;360(1):233-7. Epub 2007 Jun 14. PMID: 17585882


EGCG fights cancer by modulating telomerase activity.

The ends of human chromosomes are protected from the degradation associated with cell division by 15-20 kb long segments of hexameric repeats of 5'-TTAGGG-3' termed telomeres. In normal cells telomeres lose up to 300 bp of DNA per cell division that ultimately leads to senescence; however, most cancer cells bypass this lifespan restriction through the expression of telomerase. hTERT, the catalytic subunit essential for the proper function of telomerase, has been shown to be expressed in approximately 90% of all cancers. In this study we investigated the hTERT inhibiting effects of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea catechins, in MCF-7 breast cancers cells and HL60 promyelocytic leukemia cells. Exposure to EGCG reduced cellular proliferation and induced apoptosis in both MCF-7 and HL60 cells in vitro, although hTERT mRNA expression was decreased only in MCF-7 cells when treated with EGCG. Furthermore, down-regulation of hTERT gene expression in MCF-7 cells appeared to be largely due to epigenetic alterations. Treatment of MCF-7 cells with EGCG resulted in a time-dependent decrease in hTERT promoter methylation and ablated histone H3 Lys9 acetylation. In conjunction with demethylation, further analysis showed an increase in hTERT repressor E2F-1 binding at the promoter. From these findings, we propose that EGCG is effective in causing cell death in both MCF-7 and HL60 cancer cell lines and may work through different pathways involving both anti-oxidant effects and epigenetic modulation. (c) 2007 Wiley-Liss, Inc.  

J Ethnopharmacol. 1999 Nov 1;67(2):233-9. PMID: 17570133


Guggul inhibits both non-drug and drug-resistant cancer cells.

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.

Biochem Pharmacol. 2007 Jun 30;74(1):118-30. Epub 2007 Mar 30. PMID: 17475222


Pomegranate exhibits significant antitumor activity against human prostate cancer.

We completed a multicenter study of the effects of pomegranate cold-pressed (Oil) or supercritical CO(2)-extracted (S) seed oil, fermented juice polyphenols (W), and pericarp polyphenols (P) on human prostate cancer cell xenograft growth in vivo, and/or proliferation, cell cycle distribution, apoptosis, gene expression, and invasion across Matrigel, in vitro. Oil, W, and P each acutely inhibited in vitro proliferation of LNCaP, PC-3, and DU 145 human cancer cell lines. The dose of P required to inhibit cell proliferation of the prostate cancer cell line LNCaP by 50% (ED(50)) was 70 microg/mL, whereas normal prostate epithelial cells (hPrEC) were significantly less affected (ED(50) = 250 g/mL). These effects were mediated by changes in both cell cycle distribution and induction of apoptosis. For example, the androgen-independent cell line DU 145 showed a significant increase from 11% to 22% in G(2)/M cells (P <.05) by treatment with Oil (35 microg/mL) with a modest induction of apoptosis. In other cell lines/treatments, the apoptotic response predominated, for example, in PC-3 cells treated with P, at least partially through a caspase 3-mediated pathway. These cellular effects coincided with rapid changes in mRNA levels of gene targets. Thus, 4-hour treatment of DU 145 cells with Oil (35 microg/mL) resulted in significant 2.3 +/- 0.001-fold (mean +/- SEM) up-regulation of the cyclin-dependent kinase inhibitor p21((waf1/cip1)) (P <.01) and 0.6 +/- 0.14-fold down-regulation of c-myc (P <.05). In parallel, all agents potently suppressed PC-3 invasion through Matrigel, and furthermore P and S demonstrated potent inhibition of PC-3 xenograft growth in athymic mice. Overall, this study demonstrates significant antitumor activity of pomegranate-derived materials against human prostate cancer.

J Med Food. 2004 Fall;7(3):274-83. PMID: 15383219


Pomegranate has potent anti-aromatase activity warranting its use for human breast cancer.

Fresh organically grown pomegranates (Punica granatum L.) of the Wonderful cultivar were processed into three components: fermented juice, aqueous pericarp extract and cold-pressed or supercritical CO2-extracted seed oil. Exposure to additional solvents yielded polyphenol-rich fractions ('polyphenols') from each of the three components. Their actions, and of the crude whole oil and crude fermented and unfermented juice concentrate, were assessed in vitro for possible chemopreventive or adjuvant therapeutic potential in human breast cancer. The ability to effect a blockade of endogenous active estrogen biosynthesis was shown by polyphenols from fermented juice, pericarp, and oil, which inhibited aromatase activity by 60-80%. Fermented juice and pericarp polyphenols, and whole seed oil, inhibited 17-beta-hydroxysteroid dehydrogenase Type 1 from 34 to 79%, at concentrations ranging from 100 to 1,000 microg/ml according to seed oil >> fermented juice polyphenols > pericarp polyphenols. In a yeast estrogen screen (YES) lyophilized fresh pomegranate juice effected a 55% inhibition of the estrogenic activity of 17-beta-estradiol; whereas the lyophilized juice by itself displayed only minimal estrogenic action. Inhibition of cell lines by fermented juice and pericarp polyphenols was according to estrogen-dependent (MCF-7) >> estrogen-independent (MB-MDA-231) > normal human breast epithelial cells (MCF-10A). In both MCF-7 and MB-MDA-231 cells, fermented pomegranate juice polyphenols consistently showed about twice the anti-proliferative effect as fresh pomegranate juice polyphenols. Pomegranate seed oil effected 90% inhibition of proliferation of MCF-7 at 100 microg/ml medium, 75% inhibition of invasion of MCF-7 across a Matrigel membrane at 10 microg/ml, and 54% apoptosis in MDA-MB-435 estrogen receptor negative metastatic human breast cancer cells at 50 microg/ml. In a murine mammary gland organ culture, fermented juice polyphenols effected 47% inhibition of cancerous lesion formation induced by the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). The findings suggest that clinical trials to further assess chemopreventive and adjuvant therapeutic applications of pomegranate in human breast cancer may be warranted.

Breast Cancer Res Treat. 2002 Feb;71(3):203-17. PMID: 12002340


Resveratrol demonstrates potent antifungal activity against Candida Albicans.

Resveratrol (3,5,4'-trihydroxystilbene) is a naturally occurring, multi-biofunctional chemical existing in grapes and various other plants as a polyphenol type, and it is one of the best known natural anticancer and antiatherosclerosis reagents. In this study, we investigated the antifungal action by resveratrol in Candida albicans, which is a human infectious fungi as an agent of candidiasis. Resveratrol displayed potent fungicidal activity in an energy-dependent manner, without any hemolytic effects against human erythrocytes. It was found that the serum-induced mycelial forms, which play a crucial role in the pathogenesis of C. albicans during host tissue invasion, were disrupted by resveratrol. To understand the correlation between lethal effects and resveratrol action, we examined the physiological changes of C. albicans. A significant accumulation of intracellular trehalose was induced by stress responses to resveratrol action, and a remarkable arrest of cell-cycle processes at the S-phase in C. albicans occured. Therefore, the fungicidal effects of resveratrol demonstrate that this compound is a potential candidate as an antifungal agent in treating infectious diseases by candidal infections.

J Microbiol Biotechnol. 2007 Aug;17(8):1324-9. PMID: 18051601


Chinese Plum (Prunus salicina) may inhibit the development of breast cancer.

The goal of this study was to evaluate the anticancer effect of Prunus salicina Lindl. cv. Soldam at three maturity stages (immature, midmature and mature stages). Previous studies have shown that this fruit (plums) possesses hematopoiesis effects, prevents osteoporosis and has anti-mutagenic effects. An acetone extract of immature P. salicina Lindl. cv. Soldam fruit contained higher levels of total phenolics and condensed tannins than midmature and mature plums. The results showed that an acetone extract of immature plums possesses cytotoxic effects, which are related to the activity of the total polyphenols in the fruits. Apoptosis in MDA-MB-231 cells mediated by the immature plums was associated with an increase in Bax levels and a reduction in Bcl-2 levels and the cleavage of caspase 3, caspase 7, caspase 9 and poly-(ADP-ribose) polymerase. These results indicate that immature fruit of P . salicina Lindl. cv. Soldam can be regarded as a safe and promising new dietary source for decreasing the risk of developing breast cancer.

Int J Food Sci Nutr. 2007 Feb;58(1):42-53. PMID: 17415955


EGCG has a direct effect on growth inhibition in human esophageal cancer.

"(-)-Epigallocatechin-3-gallate (EGCG), the principal polyphenol in green tea, has been shown to inhibit the growth of many cancer cell lines and to suppress the phosphorylation of epidermal growth factor receptor (EGFR). We observed similar effects of EGCG in esophageal squamous cell carcinoma KYSE 150 cells and epidermoid squamous cell carcinoma A431 cells. Pretreatment of KYSE 150 cells with EGCG (20 micromol/L) for 0.5 to 24 hours in HAM's F12 and RPMI 1640 mixed medium at 37 degrees C, before the addition of EGF, resulted in a decreased level of phosphorylated EGFR (by 32-85%). Prolonged treatment with EGCG (8 or 24 hours) also decreased EGFR protein level (both by 80%). EGCG treatment for 24 hours also caused decreased signals of HER-2/neu in esophageal adenocarcinoma OE19 cells. These effects of EGCG were prevented or diminished by the addition of superoxide dismutase (SOD, 5 units/mL), or SOD plus catalase (30 units/mL), to the cell culture medium. A similar phenomenon on inactivation of EGFR was observed in A431 cells as well. Under culture conditions for KYSE 150 cells, EGCG was unstable, with a half-life of approximately 30 minutes; EGCG dimers and other oxidative products were formed. The presence of SOD in the culture medium stabilized EGCG and increased its half-life to longer than 24 hours and some EGCG epimerized to (+)-gallocatechin-3-gallate. A mechanism of superoxide radical-mediated dimerization of EGCG and H2O2 formation is proposed. The stabilization of EGCG by SOD in the culture medium potentiated the activity of EGCG in inhibiting KYSE 150 cell growth. The results suggest that in cell culture conditions, the auto-oxidation of EGCG leads to EGFR inactivation, but the inhibition of cell growth is due to other mechanisms. It remains to be determined whether the presently observed auto-oxidation of EGCG occurs in vivo. In future studies of EGCG and other polyphenolic compounds in cell culture, SOD may be added to stabilize EGCG and to avoid possible artifacts.

Cancer Res. 2005 Sep 1;65(17):8049-56. PMID: 16140980


Green tea inhibits lung carcinogenesis.

In order to study the biological activities of tea preparations and purified tea polyphenols, their growth inhibitory effects were investigated using four human cancer cell lines. Growth inhibition was measured by [3H]thymidine incorporation after 48 h of treatment. The green tea catechins (-)-epigallocatechin-3-gallate (EGCG) and (-)-epigallocatechin (EGC) displayed strong growth inhibitory effects against lung tumor cell lines H661 and H1299, with estimated IC50 values of 22 microM, but were less effective against lung cancer cell line H441 and colon cancer cell line HT-29 with IC50 values 2- to 3-fold higher. (-)-Epicatechin-3-gallate, had lower activities, and (-)-epicatechin was even less effective. Preparations of green tea polyphenols and theaflavins had higher activities than extracts of green tea and decaffeinated green tea. The results suggest that the growth inhibitory activity of tea extracts is caused by the activities of different tea polyphenols. Exposure of H661 cells to 30 microM EGCG, EGC or theaflavins for 24 h led to the induction of apoptosis as determined by an annexin V apoptosis assay, showing apoptosis indices of 23, 26 and 8%, respectively; with 100 microM of these compounds, the apoptosis indices were 82, 76 and 78%, respectively. Incubation of H661 cells with EGCG also induced a dose-dependent formation of H2O2. Addition of H2O2 to H661 cells caused apoptosis in a manner similar to that caused by EGCG. The EGCG-induced apoptosis in H661 cells was completely inhibited by exogenously added catalase (50 units/ml). These results suggest that tea polyphenol-induced production of H2O2 may mediate apoptosis and that this may contribute to the growth inhibitory activities of tea polyphenols in vitro..  

Carcinogenesis. 1998 Apr;19(4):611-6. PMID: 9600345


EGCG induces apoptosis in melanoma cells.

Melanoma accounts for only about 4% of all skin cancer cases but most of not been adequately effective in the management of melanoma. Therefore, novel approaches are needed for prevention and treatment of this disease. Chemoprevention by naturally occurring agents present in food and beverages has shown benefits in certain cancers including nonmelanoma skin cancers. Here, employing 2 human melanoma cell lines (A-375 amelanotic malignant melanoma and Hs-294T metastatic melanoma) and normal human epidermal melanocytes (NHEM), we studied the antiproliferative effects of epigallocatechin-3-gallate (EGCG), the major polyphenolic antioxidant present in green tea. EGCG treatment was found to result in a dose-dependent decrease in the viability and growth of both melanoma cell lines. Interestingly, at similar EGCG concentrations, the normal melanocytes were not affected. EGCG treatment of the melanoma cell lines resulted in decreased cell proliferation (as assessed by Ki-67 and PCNA protein levels) and induction of apoptosis (as assessed cleavage of PARP, TUNEL assay and JC-1 assay). EGCG also significantly inhibited the colony formation ability of the melanoma cells studied. EGCG treatment of melanoma cells resulted in a downmodulation of anti-apoptotic protein Bcl2, upregulation of proapoptotic Bax and activation of caspases -3, -7 and -9. Furthermore, our data demonstrated that EGCG treatment resulted in a significant, dose-dependent decrease in cyclin D1 and cdk2 protein levels and induction of cyclin kinase inhibitors (ckis) p16INK4a, p21WAF1/CIP1 and p27KIP1. Our data suggest that EGCG causes significant induction of cell cycle arrest and apoptosis of melanoma cells that is mediated via modulations in the cki-cyclin-cdk network and Bcl2 family proteins. Thus, EGCG, alone or in conjunction with current therapies, could be useful for the management of melanoma.

Int J Cancer. 2005 Apr 20;114(4):513-21. PMID: 15609335


Ellagic acid demonstrates anticancer activity against human neuroblastoma cells.

Ellagic acid, a polyphenolic compound found in berries, fruits and nuts, has been shown to possess growth-inhibiting and apoptosis promoting activities in cancer cell lines in vitro. The objective of this study was to investigate the effect of ellagic acid in human neuroblastoma SH-SY5Y cells. In cultures of SH-SY5Y cells incubated with ellagic acid, time- and concentration-dependent inhibitory effects on cell number were demonstrated. Ellagic acid induced cell detachment, decreased cell viability and induced apoptosis as measured by DNA strand breaks. Ellagic acid-induced alterations in cell cycle were also observed. Simultaneous treatment with all-trans retinoic acid did not rescue the cells from ellagic acid effects. Furthermore, the results suggested that pre-treatment with all-trans retinoic acid to induce differentiation and cell cycle arrest did not rescue the cells from ellagic acid-induced cell death.

Biomed Pharmacother. 2008 Sep 15. PMID: 18848760


Cranberry polyphenols sensitize platinum-resistant ovarian cancer cells to the cytotoxic effects of paraplatin.

Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A-type PACs with 1-4 linkages containing between 2-8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum-resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC(50) = 79-479 microg/mL) but were non-cytotoxic to lung fibroblast cells (IC(50) > 1000 microg/ml). SKOV-3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV-3 cells. Pretreatment of SKOV-3 cells with PACs (106 microg/ml) resulted in a significant reduction of the paraplatin IC(50) value. Similarly, in a BrdU incorporation assay, co-treatment of SKOV-3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV-3 cell cultures co-treated with PAC-1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP-8, -9, -11 and -14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell-line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum-resistant SKOV-3 ovarian cancer cells. Copyright (c) 2009 John Wiley & Sons, Ltd.

Phytother Res. 2009 Jan 26. PMID: 19172579


EGCG, a green tea polyphenol, has a multitude of therapeutic benefits in the prevention and treatment of prostate cancer.

Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-related deaths in American males. For these reasons, it is necessary to intensify our efforts for better understanding and development of novel treatment and chemopreventive approaches for this disease. In recent years, green tea has gained considerable attention as an agent that could reduce the risk of several cancer types. The cancer-chemopreventive effects of green tea appear to be mediated by the polyphenolic constituents present therein. Based on geographical observations that suggest that the incidence of PCa is lower in Japanese and Chinese populations that consume green tea on a regular basis, we hypothesized that green tea and/or its constituents could be effective for chemoprevention of PCa. To investigate this hypothesis, we initiated a program for the chemoprevention of PCa by green tea. In cell-culture systems that employ human PCa cells DU145 (androgen insensitive) and LNCaP (androgen sensitive), we found that the major polyphenolic constituent (-)-epigallocatechin-3-gallate (EGCG) of green tea induces 1) apoptosis, 2) cell-growth inhibition, and 3) cyclin kinase inhibitor WAF-1/p21-mediated cell-cycle dysregulation. More recently, using a cDNA microarray, we found that EGCG treatment of LNCaP cells results in 1) induction of genes that functionally exhibit growth-inhibitory effects, and 2) repression of genes that belong to the G-protein signaling network. In animal studies that employ a transgenic adenocarcinoma of the mouse prostate (TRAMP), which is a model that mimics progressive forms of human prostatic disease, we observed that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to 6 cups of green tea/d) significantly inhibits PCa development and metastasis. We extended these studies and more recently observed increased expression of genes related to angiogenesis such as vascular endothelial growth factor (VEGF) and those related to metastasis such as matrix metalloproteinases (MMP)-2 and MMP-9 in prostate cancer of TRAMP mice. Oral feeding of GTP as the sole source of drinking fluid to TRAMP mice results in significant inhibition of VEGF, MMP-2 and MMP-9. These data suggest that there are multiple targets for PCa chemoprevention by green tea and highlight the need for further studies to identify novel pathways that may be modulated by green tea or its polyphenolic constituents that could be further exploited for prevention and/or treatment of PCa.  

J Nutr. 2003 Jul;133(7 Suppl):2417S-2424S. PMID: 12840218


EGCG, a green tea polyphenol, encourages programmed cell death in prostate cancer cells.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising candidate for cancer therapy, however, emergence of drug resistance limits its potential use. Here, we report for the first time that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, sensitizes TRAIL-resistant LNCaP cells to TRAIL-mediated apoptosis through modulation of intrinsic and extrinsic apoptotic pathways. When combined with EGCG, Apo2L/TRAIL exhibited enhanced apoptotic activity in LNCaP cells characterized by three major molecular events. First, apoptosis induction was accompanied by the upregulation of poly(ADP-ribose) polymerase cleavage and modulation of pro- and antiapoptotic Bcl2 family of proteins. A synergistic inhibition of inhibitors of apoptosis with concomitant increase in caspase cleavage was observed. Second, pretreatment of cells with EGCG resulted in modulation of death-inducing signaling cascade complex involving DR4/TRAIL R1, Fas-associated death domain and FLICE-inhibitory protein proteins. Last, we observed a synergistic inhibition in the invasion and migration of LNCaP cells. This effect was observed to be mediated through inhibition in the protein expression of vascular endothelial growth factor, uPA and angiopoietin 1 and 2. Further, the activity and protein expression of MMP-2, -3 and -9 and upregulation of TIMP1 in cells treated with a combination of EGCG and TRAIL was observed. These data might have implications for developing new strategies aimed at eliminating prostate cancer cells resistant to TRAIL.  

Oncogene. 2008 Mar 27;27(14):2055-63. Epub 2007 Nov 12. PMID: 17998943


Wheat grass extract induces programmed cell death in colon cancer cell lines.

Wheat sprouts contain a very high level of organic phosphates and a powerful cocktail of different molecules such as enzymes, reducing glycosides and polyphenols. The antioxidant properties of wheat sprouts have been widely documented and it has been shown that they are able to protect DNA against free-radicals mediated oxidative damage. Furthermore, we have recently reported on the effects of several polyphenols on 20S proteasomes, underlying the dual role of epigallocatechin-3-gallate as an antioxidant and a proteasome effector in cancer cells. The aim of this study was to investigate the effects of wheat sprout extracts on 20S proteasome functionality. Wheat sprout extracts have been analysed and characterized for their polyphenolic content using the Folin-Ciocalteau reagent and RP-HPLC technique. Comparing our data with a polyphenol standard mixture we identified five different polyphenols: gallic acid, epigallocatechin-3-gallate, epigallocatechin, epicatechin and catechin. The treatment of isolated 20S proteasomes with the extract induced a gradual inhibition of all the tested components, ChT-L, T-L, PGPH and BrAAP, in both the complexes. At low extract concentration a slight activation of the enzyme was evident only for the BrAAP component of the constitutive enzyme and the ChT-L activity of the immunoproteasome. beta-casein degradation rate decreased, particularly with the immunoproteasome. Human Colon adenocarcinoma (Caco) cells, stimulated with 12-O-tetradecanoylphorbol-13-acetate, showed activation of the 20S proteasome activities at short incubation times and an increase in intracellular oxidative proteins. Cells treatment with wheat sprout extract led to proteasome inhibition in unstimulated cells and attenuated the effects mediated by TPA. Finally, exposure to the extract affected the expression levels of pro-apoptotic proteins.

Biochimie. 2008 May;90(5):790-801. Epub 2007 Dec 23. PMID: 18190797


Resveratrol is a bilevel inhibitor of aromatase in breast cancer cells.

Estrogen plays a crucial role in the development of breast cancer, and the inhibition of estrogen synthesis has been an important target for the prevention and treatment of this disease. The rate-limiting reaction of the hormone biosynthesis is catalyzed by cytochrome P450 (CYP) 19 enzyme or aromatase. It has been of genuine interest to uncover an aromatase-inhibitory compound from a dietary source. Resveratrol is a polyphenolic compound that can be isolated from grape peel. Because of its structural resemblance to estrogen, resveratrol's agonistic and antagonistic properties on estrogen receptor have been examined and demonstrated. In the present study, the effect of resveratrol on the expression and enzyme activity of aromatase was investigated. By assaying on MCF-7 cells stably transfected with CYP19 (MCF-7aro cells), resveratrol inhibited the aromatase activity with an IC(50) value of 25 microM. Kinetic analysis indicated that both competitive and noncompetitive inhibition might be involved. The administration of 10 nmol/l testosterone-a substrate of aromatase-produced a 50% increase in the MCF-7aro cell number. This cell proliferation specifically induced by testosterone was significantly reduced by 10 microM resveratrol. In addition, 50 microM resveratrol significantly reduced the CYP19-encoding mRNA abundance in SK-BR-3 cells. The transcriptional control of CYP19 gene is tissue specific, and promoter regions I.3 and II have previously been shown to be responsible for CYP19 expression in breast cancer cells. Luciferase reporter gene assays revealed that resveratrol could repress the transcriptional control dictated by the promoter regulation. The present study illustrated that pharmacological dosage of resveratrol inhibited aromatase at both the enzyme and mRNA levels.

Toxicol Sci. 2006 Jul;92(1):71-7. Epub 2006 Apr 11. PMID: 16611627


Artichoke extract exhibits antioxidant and apoptotic activity relevant to the treatment of human liver cancer.

Cultured rat hepatocytes and human hepatoma HepG2 cells were used to evaluate the hepatoprotective properties of polyphenolic extracts from the edible part of artichoke (AE). The hepatocytes were exposed to H2O2generated in situ by glucose oxidase and were treated with either AE, or pure chlorogenic acid (ChA) or with the well known antioxidant, N, N'-diphenyl-p-phenilenediamine (DPPD). Addition of glucose oxidase to the culture medium caused depletion of intracellular glutathione (GSH) content, accumulation of malondialdehyde (MDA) in the cultures, as a lipid peroxidation indicator, and cell death. These results demonstrated that AE protected cells from the oxidative stress caused by glucose oxidase, comparable to DPPD. Furthermore, AE, as well as ChA, prevented the loss of total GSH and the accumulation of MDA. Treatment of HepG2 cells for 24 h with AE reduced cell viability in a dose-dependent manner, however, ChA had no prominent effects on the cell death rate. Similarly, AE rather than ChA induced apoptosis, measured by flow cytometric analysis of annexin and by activation of caspase-3, in HepG2 cells. Our findings indicate that AE had a marked antioxidative potential that protects hepatocytes from an oxidative stress. Furthermore, AE reduced cell viability and had an apoptotic activity on a human liver cancer cell line.

Nutr Cancer. 2008;60(2):276-83. PMID: 18444161


Litchi fruit extract exhibits anticancer activity against human liver cancer cell lines.

Litchi fruit pericarp (LFP) extract contains significant amounts of polyphenolic compounds, and exhibits powerful antioxidative activity against fat oxidation in vitro. The purpose of this study is to confirm the anticancer activity of LFP extract against hepatocellular carcinoma in vitro and in vivo, and to elucidate the mechanism of its activity. Human hepatocellular carcinoma cell line was tested in vitro for cytotoxicity, colony formation inhibition, and cell cycle distribution through flow cytometry after treatment with water-soluble crude ethanolic extract (CEE) from LFP. Murine hepatoma bearing-mice were fed doses of 0.15, 0.3, and 0.6g/kg/day of water-soluble CEE in DH(2)O p.o. for 10 days, respectively, to test the anticancer activity and BrdU incorporation of cancer cells in vivo. LFP extract demonstrated a dose- and time-dependent inhibitory effect on cancer cell growth; IC(50) was 80microg/ml, and significantly inhibited colony formation in vitro, tumor growth and BrdU incorporation into cancer cells in vivo. The tumor inhibitory rates at doses of 0.15, 0.3, and 0.6g/kg/day were 17.31% (P>0.05), 30.77% (P<0.05), and 44.23% (P<0.01), respectively. BrdU labeled tumor cells of treated animals were 11.80+/-2.79%, and were significantly lower than that in untreated controls (23.00+/-5.42%, P<0.05). Our findings showed that LFP extract exhibited potential anticancer activity against hepatocellular carcinoma in vitro and in vivo through proliferating inhibition and apoptosis induction of cancer cells. 

J Am Mosq Control Assoc. 2006 Sep;22(3):497-500. PMID: 16300877


EGCG, a green tea polyphenol, induces programmed cell death in human lymphoblastoid B cells.

(-)-Epigallocatechin-3-gallate (EGCG), a major constituent of green tea polyphenols, has been shown to suppress cancer cell proliferation and induce apoptosis. In this study we investigated its efficacy and the mechanism underlying its effect using human B lymphoblastoid cell line Ramos, and effect of co-treatment with EGCG and a chemotherapeutic agent on apoptotic cell death. EGCG induced dose- and time-dependent apoptotic cell death accompanied by loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, and cleavage of pro-caspase-9 to its active form. EGCG also enhanced production of intracellular reactive oxygen species (ROS). Pretreatment with diphenylene iodonium chloride, an inhibitor of NAD(P)H oxidase and an antioxidant, partially suppressed both EGCG-induced apoptosis and production of ROS, implying that oxidative stress is involved in the apoptotic response. Furthermore, we showed that combined-treatment with EGCG and a chemotherapeutic agent, etoposide, synergistically induced apoptosis in Ramos cells.

Biochem Biophys Res Commun. 2007 Nov 3;362(4):951-7. Epub 2007 Aug 24. PMID: 17803956


EGCG, a green tea polyphenol, induces programmed cell death in human lymphoblastoid B cells.

PURPOSE: Green tea polyphenol, (-)-epigallocatechin-3-gallate, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of (-)-epigallocatechin-3-gallate as a novel therapeutic agent for the patients with B-cell malignancies including multiple myeloma. EXPERIMENTAL DESIGN: We investigated the effects of (-)-epigallocatechin-3-gallate on the induction of apoptosis in HS-sultan as well as myeloma cells in vitro and further examined the molecular mechanisms of (-)-epigallocatechin-3-gallate-induced apoptosis. RESULTS: (-)-Epigallocatechin-3-gallate rapidly induced apoptotic cell death in various malignant B-cell lines in a dose- and time-dependent manner. (-)-Epigallocatechin-3-gallate-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials (Deltapsim); the release of cytochrome c, Smac/DIABLO, and AIF from mitochondria into the cytosol; and the activation of caspase-3 and caspase-9. Elevation of intracellular reactive oxygen species (ROS) production was also shown during (-)-epigallocatechin-3-gallate-induced apoptosis of HS-sultan and RPMI8226 cells as well as fresh myeloma cells. Antioxidant, catalase, and Mn superoxide dismutase significantly reduced ROS production and (-)-epigallocatechin-3-gallate-induced apoptosis, suggesting that ROS plays a key role in (-)-epigallocatechin-3-gallate-induced apoptosis in B cells. Furthermore, a combination with arsenic trioxide (As2O3) and (-)-epigallocatechin-3-gallate significantly enhanced induction of apoptosis compared with As2O3 alone via decreased intracellular reduced glutathione levels and increased production of ROS. CONCLUSIONS: (-)-Epigallocatechin-3-gallate has potential as a novel therapeutic agent for patients with B-cell malignancies including multiple myeloma via induction of apoptosis mediated by modification of the redox system. In addition, (-)-epigallocatechin-3-gallate enhanced As2O3-induced apoptosis in human multiple myeloma cells.

Support Care Cancer. 2010 Jun;18(6):751-9. Epub 2009 Aug 14. PMID: 16115949


Pomegranate polyphenols have a protective effect against UVA- and UVB-induced cell damage.

Exposure to ultraviolet (UV) radiation has been associated with several acute and chronic conditions, including sunburn, edema, hyperplasia, immunosuppression, photoaging, and skin cancer. The role of naturally occurring phytochemicals in the prevention of such UV-related conditions has captured increased interest. Pomegranate ( Punica granatum L.) is a rich source of polyphenolics, which have been shown to exert anti-inflammatory, antioxidant, and anticarcinogenic activity in numerous in vivo and in vitro studies. This work investigated potential protective effects of a pomegranate fruit extract standardized to punicalagins against UVA- and UVB-induced damage in SKU-1064 human skin fibroblast cells. Pomegranate extract (PE), in a range from 5 to 60 mg/L, was effective at protecting human skin fibroblasts from cell death following UV exposure, likely related to a reduced activation of the pro-inflammatory transcription factor NF-kappaB, a downregulation of proapoptotic caspase-3, and an increased G0/G1 phase, associated with DNA repair. Higher polyphenolic concentrations (500-10000 mg/L) were needed to achieve a significant reduction in UV-induced reactive oxygen species levels and increased intracellular antioxidant capacity (from 1.9 to 8.6 muM Trolox equivalents/mL). Results from this study demonstrate the protective effects of PE against UVA- and UVB-induced cell damage and the potential use of pomegranate polyphenolics in topical applications.

J Agric Food Chem. 2008 Sep 24;56(18):8434-41. Epub 2008 Aug 22. PMID: 18717570


EGCG changes the phenotype of invasive breast cancer cells, repressing malignancy.

Previously, we showed that the bioactive green tea polyphenol epigallocatechin-3-gallate (EGCG) inhibits growth in soft agar of breast cancer cells with Her-2/neu overexpression. Using gene expression profiling, here we show that EGCG treatment of Her-2/neu-driven mammary tumor cells alters the expression of key regulators in the epithelial to mesenchymal transition (EMT) pathway, reducing invasive phenotype. Specifically, the epithelial genes E-cadherin, gamma-catenin, MTA3, and estrogen receptor alpha (ERalpha) were up-regulated by EGCG, whereas the proinvasive snail gene was down-regulated. Consistently, EGCG inhibited branching colony growth and invasion in Matrigel. EGCG treatment similarly inhibited invasive phenotype of mouse mammary tumor cells driven by Nuclear Factor-kappaB c-Rel and protein kinase CK2, frequently found overexpressed in human breast disease. Recently, we identified the Forkhead box O transcription factor FOXO3a as a major transcriptional regulator of ERalpha. Given the pivotal role of ERalpha in preventing EMT, we hypothesized that the activation of FOXO3a by EGCG plays an important role in the observed reversal of invasive phenotype in ERalpha-positive breast cancer cells. EGCG treatment activated FOXO3a. Ectopic expression of a constitutively active FOXO3a overrode transforming growth factor-beta1-mediated invasive phenotype and induced a more epithelial phenotype, which was dependent on ERalpha expression and signaling. Conversely, a dominant negative FOXO3a reduced epithelial phenotype of ERalpha-low breast cancer cells. These results identify, for the first time, a role for FOXO3a in the inhibition of invasive phenotype in breast cancer cells with active ERalpha signaling and elucidate a novel mechanism whereby EGCG represses EMT of breast cancer cells.

Cancer Res. 2007 Jun 15;67(12):5763-70. PMID: 17575143


Curcumin may have therapeutic potential for bladder cancer patients via anti-inflammatory, antioxidant and anti-carcinogenic activities.

Curcumin, a polyphenol compound derived from Curcuma longa Linn, has been recognized as a promising anti-cancer drug due to its multiple properties including anti-inflammatory, anti-oxidant and anti-carcinogenic activities. To elucidate the mechanisms by which curcumin inhibits human bladder carcinoma T24 cell proliferation, we tested the effects of curcumin on specific cell cycle pathways and on the expression of cyclooxygenases (COXs). Curcumin inhibited the growth of T24 cells and induced G2/M arrest in a concentration-dependent manner, effects associated with the down-regulation of cyclin A and up-regulation of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1). However, other G2/M regulatory molecules, such as cyclin A, Cdc2, Cdk2, Wee1 and Cdc25C, were not modulated by curcumin treatment. Furthermore, curcumin decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which correlated with a decrease in prostaglandin E2 (PGE2) synthesis. These observations suggest that curcumin may have therapeutic potential for bladder cancer patients.

Oncol Rep. 2006 May;15(5):1225-31. PMID: 16596191


Resveratrol and querctin work synergistically to inhibit glioma cell lines.

Glioma is the most frequent and malignant primary human brain tumor with dismal prognosis despite multimodal therapy. Resveratrol and quercetin, two structurally related and naturally occurring polyphenols, are proposed to have anticancer effects. We report here that resveratrol and quercetin decreased the cell number in four glioma cell lines but not in rat astrocytes. Low doses of resveratrol (10 microM) or quercetin (25 microM) separately had no effect on apoptosis induction, but had a strong effect on caspase 3/7 activation when administered together. Western blot analyses showed that resveratrol (10 microM) and quercetin (25 microM) caused a reduction in phosphorylation of Akt, but this reduction was not sufficient by itself to mediate the effects of these polyphenols. Most important, resveratrol and quercetin chronically administered presented a strong synergism in inducing senescence-like growth arrest. These results suggest that the combination of polyphenols can potentialize their antitumoral activity, thereby reducing the therapeutic concentration needed for glioma treatment. (Cancer Sci 2009).

Cancer Sci. 2009 May 12. PMID: 19496785


Curcumin induces programmed cell death in human malignant gliobastoma cells. - Article 1

Glioblastoma is the most malignant human brain tumor that shows poor response to existing therapeutic agents. Search continues for an effective therapy for controlling this deadliest brain tumor. Curcumin (CCM), a polyphenolic compound from Curcuma longa, possesses anti-cancer properties in both in vitro and in vivo. In the present investigation, we evaluated the therapeutic efficacy of CCM against human malignant glioblastoma U87MG cells. Trypan blue dye exclusion test showed decreased viability of U87MG cells with increasing dose of CCM. Wright staining and ApopTag assay, respectively, showed the morphological and biochemical features of apoptosis in U87MG cells treated with 25 microM and 50 microM of CCM for 24 h. Western blotting showed activation of caspase-8, cleavage of Bid to tBid, increase in Bax:Bcl-2 ratio, and release of cytochrome c from mitochondria followed by activation of caspase-9 and caspase-3 for apoptosis. Also, CCM treatments increased cytosolic level of Smac/Diablo to suppress the inhibitor-of-apoptosis proteins and down regulated anti-apoptotic nuclear factor kappa B (NFkappaB), favoring the apoptosis. Increased activities of calpain and caspase-3 cleaved 270 kDa alpha-spectrin at specific sites generating 145 kDa spectrin break down product (SBDP) and 120 kDa SBDP, respectively, leading to apoptosis in U87MG cells. Results show that CCM is an effective therapeutic agent for suppression of anti-apoptotic factors and activation of calpain and caspase proteolytic cascades for apoptosis in human malignant glioblastoma cells.

Neurochem Res. 2007 Dec;32(12):2103-13. Epub 2007 Jun 12. PMID: 17562168


EGCG, a green tea polyphenol, may inhibit invasive medulloblastomas.

Epigallocatechin-3-gallate (EGCG), the major green tea polyphenol, can reach the brain following oral intake and could thus act as an anti-tumoral agent targeting several key steps of brain cancer cells invasive activity. Because integrin-mediated extracellular matrix recognition is crucial during the cell adhesion processes involved in carcinogenesis, we have investigated the effects of EGCG on different cellular integrins of the pediatric brain tumor-derived medulloblastoma cell line DAOY. Using flow cytometry, we report the levels of expression of several cell surface integrins in DAOY. These include high expression of alpha2, alpha3, and beta1 integrins, as well as alphav and beta3 integrins. Moreover, we provide evidence that EGCG can antagonize DAOY cell migration specifically on collagen by increasing cell adhesive ability through specific gene and protein upregulation of the beta1 integrin subunit. Our results suggest that this naturally occurring green tea polyphenol may thus be used as a nutraceutical therapeutic agent in targeting the invasive character of medulloblastomas. Copyright 2003 Wiley-Liss, Inc.

J Cell Biochem. 2003 Nov 1;90(4):745-55. PMID: 14587030


Ellagic acid fractions from muscadine grapes induce programmed cell death in human colon cancer cells.

Possible anticancer mechanisms exerted by polyphenolic compounds contained in fruits and vegetables include antioxidant activity, the inhibition of proliferation, and the induction of apoptosis in cancer cells. This study examined the effects of four isolated polyphenolic extracts from red muscadine grapes (Vitis rotundifolia) on vital cell parameters and the induction of apoptosis in Caco-2 colon carcinoma cells. The magnitude of effects in cell culture was then correlated to polyphenolic composition and antioxidant capacity. Whereas anticancer effects of individual polyphenolic compounds have been demonstrated multiple times, information relating to anticancer effects of polyphenolic extracts is not available in abundance. All four extracts induced apoptosis, decreased cell number, and caused alterations in cell cycle kinetics in a concentration-dependent manner. The efficacy of the polyphenolics on vital cell parameters correlated well to the presence of ellagic acid glycosides and flavonoids and also to the antioxidant capacity. This study demonstrated the anticancer properties of ellagic acid rich extracts from red muscadine juice.

J Agric Food Chem. 2006 Jul 26;54(15):5336-43. PMID: 16848514


Muscadine grapes contain phenolics with anticancer activity.

Muscadine grapes have unique aroma and flavor characteristics. Although a few studies reported high polyphenols content of muscadine grapes, little research has been conducted to evaluate the phenolic compounds bioactivities in any muscadine grape cultivar. The objective of this study was to evaluate the effect of phenolic compounds in muscadine grapes on cancer cell viability and apoptosis. Four cultivars of muscadine (Carlos, Ison, Noble, and Supreme) were assessed in this study. Phenolic compounds were extracted from muscadine skins and further separated into phenolic acids, tannins, flavonols, and anthocyanins using HLB cartridge and LH20 column. Some individual phenolic acids and flavonoids were identified by HPLC. Anthocyanin fractions were more than 90% pure. The effect of different fractions on the viability and apoptosis of two colon cancer cell lines (HT-29 and Caco-2) was evaluated. A 50% inhibition of cancer cell population growth for the two cell lines was observed at concentrations of 1-7 mg/mL for crude extracts. The phenolic acid fractions showed a 50% inhibition at the level of 0.5-3 mg/mL. The greatest inhibitory activity was found in the anthocyanin fraction, with a 50% inhibition at concentrations of approximately 200 microg/mL in HT-29 and 100-300 microg/mL in Caco-2. Anthocyanin fractions also resulted in 2-4 times increase in DNA fragmentation, indicating the induction of apoptosis. These findings suggest that polyphenols from muscadine grapes may have anticancer properties.

J Agric Food Chem. 2005 Nov 2;53(22):8804-12. PMID: 16248588


Green tea extract appears to have signifcant therapeutic effects in low grade B-cell malignancies.

Green tea or its constituents have long been touted as a health promoting substance including claims it may have cancer prevention properties. We previously reported the in vitro ability of one tea polyphenol, epigallocatechin gallate (EGCG), to induce apoptotic cell death in the leukemic B-cells from a majority of patients with chronic lymphocytic leukemia (CLL). After the publication of our findings many patients with CLL and other low grade lymphomas began using over-the-counter products containing tea polyphenols despite the absence of evidence to suggest clinical benefit, definition of possible toxicities, or information on optimal dose and schedule. We have become aware of four patients with low grade B-cell malignancies seen in our clinical practice at Mayo Clinic who began, on their own initiative, oral ingestion of EGCG containing products and subsequently appeared to have an objective clinical response. Three of these four patients met criteria for partial response (PR) by standard response criteria. Although spontaneous remission/regression is occasionally observed in individuals with low grade B-cell malignancies, such events are rare. Several patients presented here had documented steady clinical, laboratory, and/or radiographic evidence of progression immediately prior to initiation of over-the-counter green tea products and then developed objective responses shortly after self-initiating this therapy. Such anecdotes highlight the need for clinical trials of tea polyphenols to define the optimal dosing, schedule, toxicities, and clinical efficacy before widespread use can be recommended. An NCI sponsored phase I/II trial of de-caffeinated green tea extracts for patients with asymptomatic, early stage CLL opened at Mayo Clinic in August 2005.

J Agric Food Chem. 2007 Dec 12;55(25):10150-5. Epub 2007 Nov 15. PMID: 16325256


Black tea polyphenol inhibits aromatase activity and attenuates tamoxifen resistance in HER2/neu transfected human breast cancer cells.

The aromatase enzyme, which converts androstenedione to oestrone, regulates the availability of oestrogen to support the growth of hormone-dependent breast tumours. In this study, we investigated the inhibitory effects of black tea polyphenols on aromatase activities. We found that black tea polyphenols, TF-1, TF-2 and TF-3, significantly inhibited rat ovarian and human placental aromatase activities. In addition, using an in vivo model, these black tea polyphenols also inhibited the proliferation induced by 100 nM dehydroepiandrosterone (DHEA) in MCF-7 cells. Transfection of HER2/neu in MCF-7 breast cancer cells appeared to be associated with an increased resistance of the cells to hormonal therapy. Interestingly, unlike the selective oestrogen receptor modulator (SERM) tamoxifen, black tea polyphenols had antiproliferation effects in breast cancer cells with hormonal resistance. The inhibitory effect of black tea polyphenols on hormone-resistant breast cancer cells suppressed the basal receptor tyrosine phosphorylation in HER2/neu-overexpressing MCF-7 cells. These findings suggest the use of black tea polyphenols may be beneficial in the chemoprevention of hormone-dependent breast tumours and represent a possible remedy to overcome hormonal resistance of hormone-independent breast tumours.

Eur J Cancer. 2004 Sep;40(14):2165-74. PMID: 15341993


EGCG, a green tea polyphenol, exhibits antiproliferative activity against pancreatic cancer cell lines in vitro.

(-)-Epigallocatechin-3-gallate [(-)-EGCG], the most abundant polyphenolic catechin in green tea, showed chemoprevention and anticancer activities. (-)-EGCG was reported to bind to the C-terminal domain of heat shock protein 90 (Hsp90). The purpose of this study is to investigate (-)-EGCG as a novel Hsp90 inhibitor to impair Hsp90 superchaperone complex for simultaneous downregulation of oncogenic proteins in pancreatic cancer cells. MTS assay showed that (-)-EGCG exhibited antiproliferative activity against pancreatic cancer cell line Mia Paca-2 in vitro with IC50 below 50 muM. (-)-EGCG increased caspase-3 activity up to 3-fold in a time- and concentration-dependent manner. Western blotting analysis demonstrated that (-)-EGCG induced downregulation of oncogenic Hsp90 client proteins by approximately 70-95%, including Akt, Cdk4, Raf-1, Her-2, and pERK. Co-immunoprecipitation showed that (-)-EGCG decreased the association of cochaperones p23 and Hsc70 with Hsp90 by more than 50%, while it had little effect on the ATP binding to Hsp90. Proteolytic fingerprinting assay confirmed direct binding between (-)-EGCG and the Hsp90 C-terminal domain. These data suggest that the binding of (-)-EGCG to Hsp90 impairs the association of Hsp90 with its cochaperones, thereby inducing degradation of Hsp90 client proteins, resulting antiproliferating effects in pancreatic cancer cells.
1: Mol Pharm. 2009 Jul-Aug;6(4):1152-9. PMID:19438225

EGCG, a green tea polyphenol, induces programmed cell death and growth arrest in pancreatic cancer cell lines.

 Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, can exert growth suppressive effect on human pancreatic cancer cells by evoking apoptotic response. EGCG-induced apoptosis of pancreatic cancer cells is accompanied by growth arrest at an earlier phase of cell cycle along with depolarization of mitochondrial membrane. In this report, using MIA PaCa-2 cells as in vitro model, we demonstrate EGCG-induced cell death involves activation of caspase-8 and disappearance of intact 21 kDa Bid protein. Furthermore, exogenous expression of dominant negative caspase-8 or dominant negative FADD significantly abrogates apoptosis inducing ability of EGCG in MIA PaCa-2 cells. RNase protection assay revealed upregulation of the members of death receptor family, thus indicating the involvement of transmembrane extrinsic signaling in this polyphenol triggered pancreatic carcinoma cell death. Based on this, we examined the effect of EGCG and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) together on pancreatic cancer cells. A synergistic increase in apoptosis and cleavage of procaspase-3 was noted. Furthermore, clonogenic cell survival assay demonstrates the significant diminishment of MIA PaCa-2 cell proliferation in the presence of both EGCG and TRAIL. This combination treatment strategy has potential therapeutic advantage for pancreatic carcinoma.

Int J Oncol. 2009 Jan;34(1):281-6. PMID: 19082499


The food-derived polyphenols quercetin, trans-resveratrol and genistein inhibit pancreatic cancer growth and prevent metastasis, in vitro.

There is increasing evidence that food-derived polyphenols have a beneficial effect for cancers. Our purpose was to determine the effect and mechanism of action of these compounds on pancreatic cancer. We measured effects of quercetin on pancreatic cancer in a nude mouse model. We also investigated the effects of quercetin, rutin, trans-resveratrol and genistein on apoptosis and underlying signaling in pancreatic carcinoma cells in vitro. Quercetin decreased primary tumor growth, increased apoptosis and prevented metastasis in a model of pancreatic cancer. In vitro quercetin and trans-resveratrol, but not rutin, markedly enhanced apoptosis, causing mitochondrial depolarization and cytochrome c release followed by caspase-3 activation. In addition, the effect of a combination of quercetin and trans-resveratrol on mitochondrial cytochrome c release and caspase-3 activity was greater than the expected additive response. The inhibition of mitochondrial permeability transition prevented cytochrome c release, caspase-3 activation and apoptosis caused by polyphenols. Nuclear factor-kappa B activity was inhibited by quercetin and trans-resveratrol, but not genistein, indicating that this transcription factor is not the only mediator of the polyphenols' effects on apoptosis. The results suggest that food-derived polyphenols inhibit pancreatic cancer growth and prevent metastasis by inducing mitochondrial dysfunction, resulting in cytochrome c release, caspase activation and apoptosis. Copyright 2002 Wiley-Liss, Inc.

Int J Cancer. 2002 Apr 10;98(5):761-9. PMID: 11920648


Ellagic acid induces programmed cell death in pancreatic cancer cells.

AIM: To determine the effect of ellagic acid on apoptosis and proliferation in pancreatic cancer cells and to determine the mechanism of the pro-survival effects of ellagic acid. METHODS: The effect of ellagic acid on apoptosis was assessed by measuring phosphatidylserine externalization, caspase activity, mitochondrial membrane potential and DNA fragmentation; and proliferation by measuring DNA thymidine incorporation. Mitochondrial membrane potential was measured in permeabilized cells, and in isolated mitochondria. Nuclear factor kappa B (NF-kappa B) activity was measured by electromobility shift assay (EMSA). RESULTS: We show that ellagic acid, a polyphenolic compound in fruits and berries, at concentrations 10 to 50 mmol/L stimulates apoptosis in human pancreatic adenocarcinoma cells. Further, ellagic acid decreases proliferation by up to 20-fold at 50 mmol/L. Ellagic acid stimulates the mitochondrial pathway of apoptosis associated with mitochondrial depolarization, cytochrome C release, and the downstream caspase activation. Ellagic acid does not directly affect mitochondria. Ellagic acid dose-dependently decreased NF-kappa B binding activity. Furthermore, inhibition of NF-kappa B activity using IkB wild type plasmid prevented the effect of ellagic acid on apoptosis. CONCLUSION: Our data indicate that ellagic acid stimulates apoptosis through inhibition of the prosurvival transcription factor NF-kappa B.

World J Gastroenterol. 2008 Jun 21;14(23):3672-80. PMID: 18595134


Gossypol, a polyphenol isolated from cottonseeds, inhibits pancreatic cancer cell growth.

OBJECTIVES: In pancreatic cancer, several important survival molecules such as EGFR, NF-kappaB, and Bcl-2 or Bcl-XL are highly activated. Thus, agents that inhibit NF-kappaB activation, together with agents that directly inhibit Bcl-2 or Bcl-XL protein function, may lead to enhanced cell killing. (-)-Gossypol, a natural polyphenolic compound isolated from cottonseeds, is a dual and potent small-molecule inhibitor of Bcl-2 and Bcl-XL proteins, with a Ki value in the 300-600 nM range for both proteins. METHODS:: The BxPC-3 human pancreatic cell line was used in this study. (-)-Gossypol was dissolved in DMSO at 20 mmol/L as stock solution, and genistein was dissolved in 0.1 M Na2CO3 to make a 10 mM stock solution. For cell viability, apoptosis, and NF-kappaB studies, MTT assay, histone/DNA ELISA, and Electrophoretic Mobility Shift Assay (EMSA) were used, respectively. Coimmunoprecipitation experiments were designed to study Bcl-XL/Bim heterodimerization, and Western blots to study cytochrome c release. RESULTS: (-)-Gossypol showed a concentration-dependent growth inhibition effect against BxPC-3 pancreatic cancer cell line and induced apoptosis with no effect on normal peripheral blood lymphocytes. Results from coimmunoprecipitation experiments indicate that the effect of (-)-gossypol is mediated, at least, in part via disrupting the heterodimerization of Bcl-XL with Bim in BxPC-3 pancreatic cancer cells. (-)-Gossypol completely disrupts Bcl-XL/Bim heterodimerization with no change in the total Bcl-XL or Bim protein, indicating that (-)-gossypol treatment does not affect the levels of Bcl-XL and Bim proteins. We have previously shown that genistein, a prominent soy isoflavone, transcriptionally down-regulates Bcl-2, Bcl-XL, VEGF, MMP-9, and uPAR via inhibiting NF-kappaB activity. In this study, genistein down-regulated NF-kappaB DNA binding activity and inhibited the growth of BxPC-3 pancreatic cancer cells. In addition, the combination of (-)-gossypol with genistein showed significantly greater growth inhibition compared with either agent alone. CONCLUSION: From these results, we conclude that inhibition of NF-kappaB activity and direct inhibition of Bcl-2 or Bcl-XL function should serve as a novel strategy for pancreatic cancer therapy.      

Pancreas. 2005 Nov;31(4):317-24. PMID: 16258364


Carotenoids from red palm and green tea polyphenols exhibit chemopreventive effects on pancreatic cancer cell lines.

The effects of alpha-carotene, beta-carotene, palm carotene, and green tea polyphenols (GTP) on the progression stage of pancreatic carcinogenesis after rapid production of ductal lesions were studied in Syrian hamsters. Dose threshold inhibitory effects were noted for beta-carotene, 25 ppm, and palm carotene, 40 ppm, which includes 24 ppm beta-carotene reducing the numbers of putative preneoplastic lesions of duct epithelial hyperplasia and atypical hyperplasia, as well as carcinoma in situ and invasive carcinomas. GTP at doses of 500 and 5000 ppm, but not 100 ppm, also significantly decreased the numbers of hyperplasia and total duct lesions. Combined administration of 40 ppm palm carotene, and 50 ppm GTP similarly inhibited the lesion development. Alpha-carotene, however, did not affect pancreatic carcinogenesis. The results suggest that chemopreventive effects are exerted by beta-carotene and GTP above critical doses and that combined administration of palm carotene and GTP might be a candidate chemoprevention strategy for pancreatic cancer in humans.

Pancreas. 1998 Jan;16(1):13-8. PMID: 9436857


Blackberry extract has anti-inflammatory, anti-oxidant and anti-proliferative activity, in vitro.

Blackberries are rich in polyphenols, including anthocyanins. Polyphenols are hypothesized to have biological activities that may impact positively on human health. In these studies, an anthocyanin-rich extract from Hull blackberries grown in Kentucky was obtained and fully characterized in terms of total anthocyanin and phenolic content, polymeric color, anthocyanin composition, and total antioxidant capacity. In vitro cell culture studies showed that the blackberry extract inhibited HT-29 colon tumor cell growth in a concentration-dependent manner with 49.2 microg of total anthocyanins/mL inhibiting HT-29 cell growth up to 66% at 72 hours. Likewise, in a concentration-dependent manner, total anthocyanin concentrations in the range of 0-40 microg/mL suppressed both high-dose (10 microg/mL) and low-dose (0.1 microg/mL) lipid A-induced interleukin-12 release from mouse bone marrow-derived dendritic cells. These results suggest that Hull blackberry extract (HBE) has potent antioxidant, antiproliferative, and anti-inflammatory activities and that HBE-formulated products may have the potential for the treatment and/or prevention of cancer and/or other inflammatory diseases.  

J Med Food. 2007 Jun;10(2):258-65. PMID: 17651061

This website is for information purposes only. By providing the information contained herein we are not diagnosing, treating, curing, mitigating, or preventing any type of disease or medical condition. Before beginning any type of natural, integrative or conventional treatment regimen, it is advisable to seek the advice of a licensed healthcare professional.

© Copyright 2008-2018, Journal Articles copyright of original owners, MeSH copyright NLM.